Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance

作者全名："Hou, Dongyao; Liu, Ruixue; Hao, Shuai; Dou, Yong; Chen, Guizhen; Liu, Liangming; Li, Tao; Cao, Yunxing; Huang, He; Duan, Chenyang"

作者地址："[Hou, Dongyao; Liu, Ruixue; Hao, Shuai; Dou, Yong; Chen, Guizhen; Huang, He; Duan, Chenyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, Chongqing, Peoples R China; [Hao, Shuai] Nanjing Univ, Jinling Hosp, Res Inst Gen Surg, Med Sch, Nanjing, Peoples R China; [Liu, Liangming; Li, Tao] Army Med Univ, Daping Hosp, Dept Shock & Transfus, State Key Lab Trauma Burns & Combined Injury, Chongqing, Peoples R China; [Cao, Yunxing] Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, Chongqing, Peoples R China; [Huang, He; Duan, Chenyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, 76 Linjiang Rd, Chongqing 400010, Peoples R China; [Cao, Yunxing] Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, 76 Linjiang Rd, Chongqing 400010, Peoples R China"

通信作者："Huang, H; Duan, CY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Anesthesiol, 76 Linjiang Rd, Chongqing 400010, Peoples R China.; Cao, YX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Intens Care Unit, 76 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：PHARMACEUTICAL BIOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001172797400001

JCR分区：Q1

影响因子：3.9

年份：2024

卷号：62

期号：1

开始页：250

结束页：260

文献类型：Article

关键词：Traditional Chinese medicine; mitochondria; sepsis; Drp1

摘要："ContextSepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection.ObjectiveTo determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality.Materials and methodsA sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 mu g/mL)-stimulated primary intestinal microvascular endothelial cells (IMVECs) and then determine NGR1's safe dosage. Groups for each model were: in vivo-a control group, a CLP-induced sepsis group, and a CLP + NGR1 treatment group (30 mg/kg/d for 3 d); in vitro-a control group, a LPS-induced sepsis group, and a LPS + NGR1 treatment group (4 mu M for 30 min). NGR1's effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated.ResultsSepsis resulted in approximately 60% mortality within 7 days post-CLP, with significant reductions in intestinal microvascular perfusion and increases in vascular leakage. Severe mitochondrial quality imbalance was observed in IMVECs. NGR1 (IC50 is 854.1 mu M at 30 min) targeted Drp1, inhibiting mitochondrial translocation, preventing mitochondrial fragmentation and restoring IMVEC morphology and function, thus protecting against intestinal barrier dysfunction, vascular permeability, microcirculatory flow, and improving sepsis prognosis.Discussion and conclusionsDrp1-mediated mitochondrial quality imbalance is a potential therapeutic target for sepsis. Small molecule natural drugs like NGR1 targeting Drp1 may offer new directions for organ protection following sepsis. Future research should focus on clinical trials to evaluate NGR1's efficacy across various patient populations, potentially leading to novel treatments for sepsis."

基金机构："National Natural Science Foundation of China [82272252, 82372192]; Chongqing Talents Program [cstc2022ycjh-bgzxm0007]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University"

基金资助正文："This work was supported by the National Natural Science Foundation of China under grant number 82272252 and 82372192, Chongqing Talents Program under grant number (cstc2022ycjh-bgzxm0007), and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University."