Department of Geriatric Intensive Care Unit, The First Affiliated Hospital of Kunming Medical University, Yunnan Geriatric Medical Center, No.295, Xichang Road, Wuhua District, Kunming, 650032, Yunnan Province, People's Republic of China.
Department of Stomatology, The First People's Hospital of Yunnan Province, Kunming, 650034, Yunnan Province, People's Republic of China.
AAPS J. 2024 Apr 15;26(3):47. doi: 10.1208/s12248-024-00919-5.
Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated.
Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 mA level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP.
Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression mA-YTHDF1 dependently. As expected, Rg1's mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats.
Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an mA-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.
脓毒症诱导的急性肺损伤（ALI）是脓毒症的严重危及生命的并发症之一，其病理与线粒体功能障碍有关。人参皂苷 Rg1 对 ALI 具有良好的治疗作用。在此，研究了 Rg1 对脓毒症诱导的 ALI 的药理作用。
采用 CLP 手术和 LPS 处理建立脓毒症诱导的 ALI 模型。采用 HE 染色分析肺组织病理变化。采用 RT-qPCR 和 ELISA 检测细胞因子的表达和分泌。通过 MTT 测定法、流式细胞术和 TUNEL 染色评估细胞活力和凋亡。使用 DHE 探针和 JC-1 染色分别分析 ROS 水平和线粒体膜电位（MMP）。采用 MeRIP 测定法评估 FBXO3 mA 水平。通过 Co-IP 或 RIP 分析 FBXO3、YTHDF1 和 PGC-1α 之间的相互作用。
Rg1 给药可剂量依赖性地改善 LPS 诱导的上皮细胞炎症、凋亡和线粒体功能障碍。在机制上，Rg1 通过抑制 FBXO3 表达 mA-YTHDF1 依赖性来降低 PGC-1α 泛素化修饰水平。正如预期的那样，FBXO3 的过表达消除了 Rg1 对 LPS 诱导的肺上皮细胞炎症、凋亡和线粒体功能障碍的缓解作用。此外，FBXO3 的上调消除了 Rg1 对 CLP 诱导的大鼠肺损伤的恢复作用。
Rg1 通过降低 mA-YTHDF1 依赖性 FBXO3 的稳定性，激活 PGC-1α/Nrf2 信号通路，改善脓毒症诱导的 ALI 进展过程中肺上皮细胞的线粒体功能。
