Objective To explore the effect of Schisandrin B (Sch B) on nuclear transcription factor E2-related factor 2 (Nrf2)/kelch-like epichlorohydrin-associated protein (Keap-1)/ peroxisome proliferation-activated receptor γ coactivator-1α (PGC-1α) signaling pathway in lung tissue of rats with severe pneumonia. Methods A rat model of severe pneumonia was first established and then randomly divided into model group, Sch B low, medium, and high dose groups and positive control group, with 10 rats in each group, and another 10 rats was selected as a blank control group. Sch B low, medium and high dose groups were given intragastrically with 2.50, 5.0, 10.0 mg/kg Sch B for intervention, the positive control group was given 1.04 mg/kg dexamethasone for intervention, and the rest of groups were given equal volume of normal saline, for 14 consecutive days. Aorta blood was taken to detect blood gas index. Lung tissue was isolated, and pathological changes, inflammatory factors and pathway-related protein expression were detected. Results The rats in the control group had normal diet, no abnormal mental state, and clear lung tissue structure. Compared with the control group, the rats in the model group were in a worse state, with symptoms such as unresponsiveness, sluggishness, and shortness of breath, inflammatory infiltration of the lung tissue, edema of the alveolar interstitium, and thickening of the alveolar wall. The PaCO2 value, TNF-α, IL-6 and IL-1β contents, Keap-1 protein expression all increased significantly (P<0.05), the PaO2 and SaO2 levels, Nrf2 and PGC-1ɑ protein expression reduced significantly (P<0.05). Compared with the model group, the adverse symptoms of rats in the Sch B low, medium, and high dose groups alleviated gradually, and the inflammatory infiltration of lung tissue and alveolar interstitial edema reduced gradually, the PaCO2 value, TNF-ɑ, IL-6 and IL-1β contents, and Keap-1 protein expression all decreased sequentially (P<0.05), the PaO2 and SaO2 values, Nrf2 and PGC-1ɑ protein expression levels increased sequentially (P<0.05). The indicators were no significant difference between the Sch B high-dose group and the positive control group (P>0.05). Conclusions Sch B can alleviate the adverse symptoms of severe pneumonia caused by Klebsiella in rats, which may be related to the activation of the NRF2/PGC-1α signaling pathway and the reduction of Keap1 protein expression.

目的：探讨苍术素（ATR）通过调节受体相互作用蛋白激酶（RIPK）1/RIPK3/混合谱系激酶结构域样（MLKL）信号通路对非小细胞肺癌（NSCLC）A549细胞程序性死亡及裸鼠移植瘤生长的影响。方法：使用0~160 μmol/L的ATR处理A549细胞，MTT法检测细胞存活率以确定后续实验给药浓度。使用ATR和/或RIPK1抑制剂Nec-1（necrostatin-1）、caspase抑制剂Z-VAD-FMK处理A549细胞，验证ATR是否诱导A549细胞发生程序性坏死。将A549细胞分为对照组、ATR-L组、ATR-M组、ATR-H组（分别用0、10、20、40 μmol/L ATR处理）、ATR+Nec-1组（40 μmol/L ATR+50 μmol/L Nec-1处理），处理24 h后，采用PI单染及Hoechst33342/PI双染法检测细胞死亡情况、透射电镜观察细胞死亡形态、DCFH-DA荧光探针法检测细胞内ROS水平、JC-1染色法检测线粒体膜电位、WB法检测细胞中RIPK1/RIPK3/MLKL信号通路相关蛋白质的表达水平。构建A549细胞裸鼠移植瘤模型，用10 mg/kg ATR（溶于玉米油中）对裸鼠灌胃给药5周，观察ATR对移植瘤生长的影响，WB法检测移植瘤组织中RIPK1/RIPK3/MLKL信号通路相关蛋白质的表达水平。结果：10~160 μmol/L的ATR可显著抑制A549细胞增殖，选择10、20、40 μmol/L的ATR进行后续实验。ATR组A549细胞存活率显著低于对照组（P<0.01）和ATR+Nec-1组（P<0.01），而ATR+z-VAD组细胞存活率显著低于z-VAD组（P<0.01），说明ATR可诱导A549细胞发生程序性坏死而非凋亡。与对照组比较，ATR处理组A549细胞发生肿胀，线粒体内脊消失呈空泡化，细胞内容物向外泄漏，细胞核聚集，表现为坏死特征，ATR-L组、ATR-M组、ATR-H组A549细胞死亡率、ROS水平及p-RIPK1、p-RIPK3、p-MLKL表达水平均显著升高，线粒体膜电位显著降低（均P<0.01），且呈药物浓度依赖性；与ATR-H组比较，ATR+Nec-1组细胞死亡率、ROS及p-RIPK1、p-RIPK3、p-MLKL表达水平降低，线粒体膜电位显著升高（均P<0.01）。裸鼠移植瘤实验结果显示，与对照组比较，ATR组裸鼠移植瘤体积、移植瘤质量均降低（P<0.05，或P<0.01），而与瘤组织中p-RIPK1、p-RIPK3、p-MLKL蛋白表达水平均显著升高（均P<0.01）。结论：ATR可能通过激活RIPK1/RIPK3/MLKL信号通路诱导A549细胞发生程序性坏死，抑制A549细胞及其裸鼠移植瘤的生长。