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

Abstract

Context

Sepsis can result in critical organ failure, and notoginsenoside R1 (NGR1) offers mitochondrial protection.

Objective

To determine whether NGR1 improves organ function and prognosis after sepsis by protecting mitochondrial quality.

Materials and methods

A sepsis model was established in C57BL/6 mice using cecum ligation puncture (CLP) and an in vitro model with lipopolysaccharide (LPS, 10 µg/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 μM for 30 min). NGR1’s effects on survival, intestinal function, mitochondrial quality, and mitochondrial dynamic-related protein (Drp1) were evaluated.

Results

Sepsis 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 μM 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 conclusions

Drp1-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.

Keywords:

• Traditional Chinese medicine
• mitochondria
• sepsis
• Drp1

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets of this study can be found at https://www.jianguoyun.com/p/DVeURM0QtMvLChjY0fUEIAA.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

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.