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Ginsenoside Rg1 Alleviates Sepsis-Induced Acute Lung Injury by Reducing FBXO3 Stability in an m6A-Dependent Manner to Activate PGC-1α/Nrf2 Signaling Pathway

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Abstract

Background

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.

Methods

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 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP.

Results

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 m6A-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.

Conclusion

Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ALI:

Acute lung injury

ARDS:

Acute respiratory distress syndrome

FBXO3:

F-Box Protein 3

PGC:

Peroxisome proliferator-activated receptor-γ coactivator

NRF2:

Nuclear factor erythroid 2-related factor 2

MTT:

3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide

ROS:

Reactive oxygen species

DHE:

Dihydroethidium

ELISA:

Enzyme-linked immunosorbent assay

ATP:

Adenosine triphosphate

IL:

Interleukin

TNF:

Tumor necrosis factor

Co-IP:

Coimmunoprecipitation

MeRIP:

Methylated RNA immunoprecipitation

CLP:

Cecal ligation and puncture

HE:

Hematoxylin-eosin

m6A:

N6-methyladenosine

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

RT-qPCR:

Real-time quantitative polymerase chain reaction

Bcl-2:

B-cell lymphoma-2

CYCS:

Cytochrome C

NDUFC2:

NADH dehydrogenase ubiquinone oxidoreductase subunit C2

YTHDF1:

YTH N6-methyladenosine RNA binding protein 1

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Funding

This work was supported by Clinical Research Center for Geriatric Diseases of Yunnan Province—diagnosis and treatment of geriatric comorbidity and clinical translational research (202102AA310069), Special Fund of Applied Basic Research of Yunnan Science and Technology Department and Kunming Medical University (202101AY07001-019).

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Authors and Affiliations

  1. 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

    Rong Liu, Qiang Wang, Jiefu Tang & Jiafei Lu

  2. Department of Stomatology, The First People’s Hospital of Yunnan Province, Kunming, 650034, Yunnan Province, People’s Republic of China

    Yao Li

  3. Department of Reproductive Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan Province, People’s Republic of China

    Ruixue Wan

  4. Department of Anatomy and Histology, School of Basic Medical Sciences, Kunming Medical University, Kunming, 650500, Yunnan Province, People’s Republic of China

    Ping Yang

  5. Department of Emergency Room of Internal, The First People’s Hospital of Yunnan Province, Kunming, 650034, Yunnan Province, People’s Republic of China

    Dexing Yang

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  1. Rong Liu
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Contributions

Rong Liu and Qiang Wang designed this study. Yao Li, Ruixue Wan, Ping Yang, Dexing Yang, Jiefu Tang, and Jiafei Lu collected the materials and performed the experiments. Rong Liu and Qiang Wang analyzed the data and wrote the manuscript. Rong Liu revised the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Rong Liu.

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All experimental procedures were approved by The First Affiliated Hospital of Kunming Medical University, Yunnan Geriatric Medical Center.

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Liu, R., Wang, Q., Li, Y. et al. Ginsenoside Rg1 Alleviates Sepsis-Induced Acute Lung Injury by Reducing FBXO3 Stability in an m6A-Dependent Manner to Activate PGC-1α/Nrf2 Signaling Pathway. AAPS J 26, 47 (2024). https://doi.org/10.1208/s12248-024-00919-5

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