Zhao Mantong, Lin Jiazi, Wang Xiao, Chen Chengkai, Li Jianhua, Yu Jiamin, Zhou Tong, Liang Yefang, Shen Xuejuan, Shi Ruixiang, Yang Simin, Zeng Shuting, Deng Yongan, Duan Xiaodong, Zhou Lichang, Sun Xiaobo, Wang Yi, Shu Zunpeng
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, Faculty of Arts and Sciences, Beijing Normal University, Zhuhai, 519087, China; School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Ruyuan Yao Autonomous County Agricultural Technology Promotion Center, Shaoguan, 512700, China.
Free Radic Biol Med. 2024 Nov 20;225:302-315. doi: 10.1016/j.freeradbiomed.2024.09.053. Epub 2024 Oct 5.
Acute lung injury (ALI) is currently a global health concern. Nicandra physalodes (L.) Gaertn. (NP) holds an important position in traditional Chinese medicine and nutrition. The potential protective mechanisms of NP against ALI remain unknown. The purpose of this study was to investigate the protective effects and molecular mechanisms of NP extract (NPE) on lipopolysaccharide (LPS)-induced ALI in mice. By utilizing network pharmacology to forecast the active ingredients in NP as well as possible signaling pathways. The composition of the NPE was analyzed using UPLC-Q-TOF-MS/MS. In addition, H-NMR immunometabolomics was employed to identify alterations in primary metabolic pathways and metabolites in the lung, serum, and fecal tissues. Finally, the protein and gene expression of key pathways were verified by IHC, IF, RT-qPCR, and ELISA. It was found that the main ingredients of NPE were revealed to be nicandrenone, withanolide A, and baicalin. NPE significantly improved lung injury, pulmonary edema, and inflammatory cell infiltration in mice with ALI. In addition, NPE improved autophagic activity and alleviated Th1 and Th17 cell-induced lung inflammation by suppressing the PI3K/Akt/mTOR signaling pathway. Importantly, immunometabolomic analysis of fecal, serum, and lung tissues revealed that NPE reversed ALI-induced leucine resistance by remodeling immunometabolism. We confirmed NPE prevents ALI by remodeling immunometabolism, regulating the Leucine/PI3K/Akt/mTOR signaling pathway, inhibiting Th1/Th17 cell differentiation, and providing a scientific immunological basis for the clinical application of NPE.
急性肺损伤（ALI）是当前全球关注的健康问题。假酸浆（Nicandra physalodes (L.) Gaertn.，NP）在传统中医和营养领域占据重要地位。NP对ALI的潜在保护机制尚不清楚。本研究旨在探讨NP提取物（NPE）对脂多糖（LPS）诱导的小鼠ALI的保护作用及分子机制。通过网络药理学预测NP中的活性成分以及可能的信号通路。采用超高效液相色谱-四极杆飞行时间串联质谱（UPLC-Q-TOF-MS/MS）分析NPE的成分。此外，利用氢核磁共振免疫代谢组学鉴定肺、血清和粪便组织中主要代谢途径和代谢物的变化。最后，通过免疫组化（IHC）、免疫荧光（IF）、实时定量聚合酶链反应（RT-qPCR）和酶联免疫吸附测定（ELISA）验证关键通路的蛋白质和基因表达。结果发现，NPE的主要成分是假酸浆烯酮、睡茄内酯A和黄芩苷。NPE显著改善了ALI小鼠的肺损伤、肺水肿和炎症细胞浸润。此外，NPE通过抑制PI3K/Akt/mTOR信号通路改善自噬活性并减轻Th1和Th17细胞诱导的肺部炎症。重要的是，对粪便、血清和肺组织的免疫代谢组学分析表明，NPE通过重塑免疫代谢逆转了ALI诱导的亮氨酸抵抗。我们证实NPE通过重塑免疫代谢、调节亮氨酸/PI3K/Akt/mTOR信号通路、抑制Th1/Th17细胞分化来预防ALI，并为NPE的临床应用提供了科学的免疫学依据。
