Li Bei, Zhang Yong, Liu Xinyuan, Zhang Ziyang, Zhuang Shuqing, Zhong Xiaoli, Chen Wenbo, Hong Yilin, Mo Pingli, Lin Shuhai, Wang Shicong, Yu Chundong
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
Department of Cardiology, Xiamen Key Laboratory of Cardiac Electrophysiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
J Pharm Anal. 2024 Apr;14(4):100915. doi: 10.1016/j.jpha.2023.12.005. Epub 2023 Dec 10.
Pien Tze Huang (PZH), a class I nationally protected traditional Chinese medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.
片仔癀（PZH）是国家一级保护的传统中药，已被用于治疗肝炎等肝脏疾病；然而，PZH对脓毒症进展的影响尚不清楚。在此，我们报道PZH可减轻小鼠脂多糖（LPS）诱导的脓毒症，并通过抑制丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路的激活，减少LPS诱导的巨噬细胞中促炎细胞因子的产生。机制上，PZH刺激信号转导和转录激活因子3（STAT3）磷酸化以诱导A20的表达，A20可抑制NF-κB和MAPK信号通路的激活。巨噬细胞中胆汁酸（BA）受体G蛋白偶联胆汁酸受体1（TGR5）的敲低消除了PZH对STAT3磷酸化和A20诱导的影响，以及LPS诱导的炎症反应，表明PZH中的胆汁酸可能通过激活TGR5介导其抗炎作用。一致地，用消胆胺树脂去除PZH中的胆汁酸可降低PZH对磷酸化STAT3和A20表达、NF-κB和MAPK信号通路激活以及促炎细胞因子产生的影响，而向消胆胺树脂处理的PZH中添加胆汁酸可部分恢复对促炎细胞因子产生的抑制作用。总体而言，我们的研究确定胆汁酸是PZH中的有效成分，其激活TGR5-STAT3-A20信号通路以改善LPS诱导的脓毒症。
