当前位置: X-MOL 学术Acta Pharm. Sin. B › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling
Acta Pharmaceutica Sinica B ( IF 14.5 ) Pub Date : 2020-07-31 , DOI: 10.1016/j.apsb.2020.07.014
Jiezhou Ye , Bo Zeng , Meiyan Zhong , Hongchun Li , Lihui Xu , Junxiang Shu , Yaofeng Wang , Fan Yang , Chunsu Zhong , Xunjia Ye , Xianhui He , Dongyun Ouyang

Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis that has critical role in defensing against bacterial infection, whereas its excess activation under pathogenic circumstances may cause various inflammatory diseases. However, there are few known drugs that can control caspase-11 activation. We report here that scutellarin, a flavonoid from Erigeron breviscapus, acted as an inhibitor for caspase-11 activation in macrophages. Scutellarin dose-dependently inhibited intracellular LPS-induced release of caspase-11p26 (indicative of caspase-11 activation) and generation of N-terminal fragment of gasdermin D (GSDMD-NT), leading to reduced pyroptosis. It also suppressed the activation of non-canonical nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as evidenced by reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and decreased interleukin-1 beta (IL-1β) and caspase-1p10 secretion, whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1β and caspase-1p10 release and ASC speck formation but not pyroptosis. Scutellarin also suppressed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells lacking ASC expression. Moreover, scutellarin treatment increased Ser/Thr phosphorylation of caspase-11 at protein kinase A (PKA)-specific sites, and its inhibitory action on caspase-11 activation was largely abrogated by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330A. Collectively, our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.



中文翻译:

黄cut素通过调节PKA信号传导抑制巨噬细胞中caspase-11的活化和焦磷酸化

炎症性caspase-11可以感知并被细胞内脂多糖(LPS)激活,从而导致细胞凋亡,这在防御细菌感染方面起着至关重要的作用,而其在病原体环境下的过度激活可能导致各种炎症性疾病。但是,几乎没有已知的药物可以控制caspase-11的活化。我们在这里报告scutellarin,灯盏花的黄酮类化合物,作为巨噬细胞中caspase-11激活的抑制剂。黄cut素剂量依赖性地抑制细胞内LPS诱导的caspase-11p26释放(表明caspase-11活化)和胃泌素D(GSDMD-NT)的N端片段的产生,从而导致黄热病减少。它也抑制包含3(NLRP3)炎性小体的非规范核苷酸结合寡聚域样受体家族吡喃结构域的激活,这由减少的凋亡相关斑点样蛋白(包含CARD(ASC)斑点形成)和减少的白介素-1所证明。 β(IL- )和caspase-1p10分泌,而NLRP3特异性抑制剂MCC950仅抑制IL- 和caspase-1p10释放和ASC斑点形成,但不发烧。黄cut苷还可以在缺乏ASC表达的RAW 264.7细胞中抑制LPS诱导的caspase-11活化和细胞凋亡。此外,盾cut处理增加了蛋白激酶A(PKA)特异性位点上caspase-11的Ser / Thr磷酸化,PKA抑制剂H89或腺苷酸环化酶抑制剂MDL12330A大大废除了其对caspase-11活化的抑制作用。总体而言,我们的数据表明,黄cut苷至少部分地通过调节PKA信号通路来抑制巨噬细胞中的caspase-11活化和焦磷酸化。

更新日期:2020-07-31
down
wechat
bug