The discovery of potentially active diterpenoids to inhibit the pyroptosis from Callicarpa arborea.
The discovery of potentially active diterpenoids to inhibit the pyroptosis from Callicarpa arborea.
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发现具有抑制木紫珠焦亡作用的潜在活性二萜类化合物。
DOI：
10.1016/j.bioorg.2022.106022
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发表时间：
2022-07
影响因子：
5.1
通讯作者：
Weilie Xiao
中科院分区：
文献类型：
--
作者：
Debing Pu;Jing Lin;Xiaojia Pu;Qi Wang;Xiaoning Li;Yan Qi;Xiaosi Li;Xiaoli Li;Ruihan Zhang;Xingjie Zhang;Chunping Wan;Weilie Xiao
上睑下垂是一种程序性炎症细胞死亡，导致炎症细胞内容物的释放和炎症的形成。失控的上睑下垂可导致严重的免疫疾病，如细胞因子释放综合征(CRS)、脓毒症、弥散性血管内凝血(DIC)以及急性器官损害，包括急性呼吸窘迫综合征(ARDS)和急性肾损伤(AKI)。紫珠属植物是传统中药的重要原料，广泛用于止痛、止血和抗炎。以前，我们已经报道了一些紫珠中的内酯二萜类化合物，它们具有很强的抑制下垂的作用。在本研究中，我们继续对这类二萜类化合物进行了研究，从紫珠中分离得到66个内酯类二萜类化合物，其中包括52个新化合物。用光谱分析、静电圆二色谱(ECD)和X-射线衍射法对它们的结构进行了表征，分别为5/6-(1-25)或6/6-(26-66)-稠合双环支架。通过检测J771A.1细胞分泌IL-1β的活性，筛选出28个化合物的IC_(50)低于10.5μM。化合物1的抑制活性最强，IC_(50)为0.68μM，并通过阻断NLRP3的炎性小体激活而抑制J774A.1巨噬细胞的松弛。体内实验进一步表明，化合物1可减少CD11b+F4/80+巨噬细胞向肺内的渗透，减轻脂多糖(LPS)诱导的肺损伤。综上所述，本研究表明化合物1具有潜在的治疗热下垂相关炎症的潜力，并为进一步开发紫珠属植物作为中草药提供了化学和药理学基础。
Pyroptosis is a programmed-inflammatory cell death, which leads to release of inflammatory cellular contents and formation of inflammation. Uncontrollable pyroptosis can result in serious immune diseases, such as cytokine release syndrome (CRS), sepsis, disseminated intravascular coagulation (DIC), and acute organ damage, including acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). Members of the Callicarpa genus are significant raw materials for traditional Chinese medicine, widely used for analgesia, hemostasis, and anti-inflammation. Previously, we have reported some ent-clerodane diterpenoids from Callicarpa arborea, shown potent inhibitory effects against pyroptosis. In this study, we went on investigating this kind of diterpenoids, and yielded 66 ent-clerodane diterpenoids, including 52 new compounds, from Callicarpa arborea. Their structures featured with a 5/6- (1-25) or a 6/6- (26-66)-fused double-ring scaffolds, were elucidated using spectroscopic data, electrostatic circular dichroism (ECD) and X-ray diffraction analyses. Screening for the inhibitory activity against pyroptosis by detecting of IL-1β secretion in J771A.1 cells, revealed 28 compounds with an IC50 below 10.5 μM. Compound 1 was the most potent with an IC50 of 0.68 μM and inhibited the J774A.1 macrophage pyroptosis by blocking the NLR pyrin domain containing 3 (NLRP3) inflammasome activation. An in vivo study further revealed that compound 1 decreased infiltration of CD11b + F4/80 + macrophages into lung and attenuated the lipopolysaccharide (LPS)-induced lung injury. Taken together, this study indicated the potential of compound 1 as a candidate for pyroptosis-related inflammation treatment, as well as provided the chemical and pharmacological basis for the further development of Callicarpa genus as a herbal medicine.
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影响因子：
4.4
作者：
Stack, JH;Beaumont, K;Hoffman, HM
通讯作者：
Hoffman, HM
DOI：
10.1038/s41573-021-00154-z
发表时间：
2021-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Liu X;Xia S;Zhang Z;Wu H;Lieberman J
通讯作者：
Lieberman J
DOI：
10.1107/s2053229614024929
发表时间：
2015-01-01
影响因子：
0.8
作者：
Spek, Anthony L.
通讯作者：
Spek, Anthony L.
影响因子：
5.1
作者：
Xu, J;Harrison, LJ;Goh, SH
通讯作者：
Goh, SH
影响因子：
5.1
作者：
Pu, De-Bing;Zhang, Xing-Jie;Xiao, Wei-Lie
通讯作者：
Xiao, Wei-Lie