Di Qianqian, Zhao Xibao, Zhang Ruihan, Ma Xingyu, Liang Xinxin, Li Xiaoli, Gao Junbo, Tang Haimei, Chen Weilin, Xiao Weilie
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Shenzhen University School of Medicine, Shenzhen, 518060, China.
Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China.
Pharmacol Res. 2021 Feb;164:105386. doi: 10.1016/j.phrs.2020.105386. Epub 2020 Dec 19.
Cellular inflammation is the underlying cause of several diseases and development of a safe and effective anti-inflammatory drug is need-of-the hour for treatment of diseases like lung inflammation. Callicarpa integerrima Champ. is a well-known herbal medicine with hemostatic and anti-inflammatory functions. However, the exact ingredient exhibiting anti-inflammatory activity in C. integerrima Champ. is largely unknown. Here, we first isolated, purified and characterized a novel clerodane-type diterpenoid Cintelactone A (CA) from C. integerrima Champ. We demonstrated that CA could significantly inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators production both in mouse peritoneal macrophages and THP1 cells. Consistently, CA also relieved inflammation and reduced LPS-induced lung injury in mice. We systematically elucidated the mechanism of action as well. CA interacted with Arg78 of tumor necrosis factor receptor-associated factor 6 (TRAF6) by hydrogen bonding. It further promoted the K48-linked ubiquitination and proteasomal degradation of TRAF6, and suppressed the activation of NF-κB and MAPKs signaling pathways. Collectively, our study reveals that new clerodane-type diterpenoid CA suppresses LPS-induced inflammation by promoting TRAF6 degradation, suggesting that CA as the potential therapeutic candidate for the treatment of inflammation associated diseases.
细胞炎症是多种疾病的根本原因，开发一种安全有效的抗炎药物对于治疗诸如肺部炎症等疾病来说是当务之急。全缘叶紫珠是一种具有止血和抗炎功能的知名草药。然而，全缘叶紫珠中表现出抗炎活性的确切成分在很大程度上尚不清楚。在此，我们首次从全缘叶紫珠中分离、纯化并鉴定了一种新型克罗烷型二萜——紫珠内酯A（CA）。我们证明，CA在小鼠腹腔巨噬细胞和THP1细胞中均可显著抑制脂多糖（LPS）诱导的促炎细胞因子和介质的产生。同样，CA也可减轻小鼠的炎症并减少LPS诱导的肺损伤。我们还系统地阐明了其作用机制。CA通过氢键与肿瘤坏死因子受体相关因子6（TRAF6）的Arg78相互作用。它进一步促进TRAF6的K48连接的泛素化和蛋白酶体降解，并抑制NF-κB和MAPKs信号通路的激活。总体而言，我们的研究表明，新型克罗烷型二萜CA通过促进TRAF6降解来抑制LPS诱导的炎症，这表明CA作为治疗炎症相关疾病的潜在治疗候选物。
