Andrographolide prevents necroptosis by suppressing the generation of reactive oxygen species.

IF 3.3 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
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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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.

穿心莲内酯通过抑制活性氧的产生来防止坏死性下垂。
穿心莲内酯(Andrographolide, Andro)是从中药穿心莲(Andrographis paniculata)中提取的天然产物,已被用于治疗多种炎症性疾病。然而,它对坏死性上睑下垂(一种与各种炎症疾病有关的细胞死亡的溶解形式)的影响仍未明确。在本研究中,我们研究了安德罗及其衍生物是否能抑制坏死性坏死。我们的研究结果表明,在脂多糖(LPS)加IDN-6556或TNF-α、LCL-161 (Smac模拟物)和IDN-6556联合诱导的体外细胞模型中,Andro显著抑制坏死下垂。在这些细胞模型中,安德罗抑制受体相互作用蛋白激酶1 (RIPK1)、RIPK3和混合谱系激酶结构域样假激酶(MLKL)的磷酸化,以及坏死体的形成。具体来说,Andro降低了细胞内活性氧(ROS)和线粒体超氧化物(mtROS)的水平,在坏死诱导过程中保留了线粒体膜电位,并激活了抗氧化转录因子核因子e2相关因子2 (Nrf2)。在坏死刺激下,一些线粒体蛋白,如Bcl-2和Bak,在坏死小体中与RIPK1、RIPK3和磷酸化的MLKL (p-MLKL)齐聚并共定位。然而,这个坏死性形成的过程可以被安德罗阻止。相反,其衍生物,包括脱氢穿心莲内酯、新穿心莲内酯、14-脱氧-11、12-二脱氢穿心莲内酯和14-脱氧穿心莲内酯,没有抗坏死性坏死的作用,也不能上调Nrf2。总之,我们的研究结果表明,安德罗特异性抑制RIPK1/RIPK3/MLKL信号轴抑制坏死性下垂,突出其治疗坏死性下垂相关疾病的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta biochimica et biophysica Sinica
Acta biochimica et biophysica Sinica 生物-生化与分子生物学
CiteScore
5.00
自引率
5.40%
发文量
170
审稿时长
3 months
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.
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