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Integrating network pharmacology and experimental models to identify notoginsenoside R1 ameliorates atherosclerosis by inhibiting macrophage NLRP3 inflammasome activation

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Abstract

Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein–protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE−/−) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1β pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1β, and IL-18, in vivo and in vitro.

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Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Abbreviations

ApoE− / − :

Apolipoprotein E-deficient;

AS:

Atherosclerosis;

BP:

Biological process;

CC:

Cellular component;

HDL-C:

High-density lipoprotein cholesterol;

H&E:

Hematoxylin–eosin;

HFD:

High-fat diet;

IL-1β:

Interleukin-1 beta;

IL-18:

Interleukin-18;

IL-6:

Interleukin-6;

LDL-C:

Low-density lipoprotein cholesterol;

MF:

Molecular function;

NGR1:

Notoginsenoside R1;

ox-LDL:

Oxidized low-density lipoprotein;

PFA:

Paraformaldehyde;

PPI:

Protein–protein interaction;

TC:

Cholesterol;

TG:

Triacylglycerides;

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

None.

Funding

This study was partly supported by the Science and Technology Project of Jiangxi Provincial Department of Education (GJJ2201302), the Graduate Innovation Special Fund Project (YC2021-X21), the Undergraduate Innovation Special Fund Project (S202311318080X), and supported by the funding from Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases (2022TMCK001).

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Authors and Affiliations

  1. School of Pharmacy, Jiangxi Science and Technology Normal University, Nanchang, 330013, China

    Jingyue Yu, Jinyu Hu, Huan Lei, Lei Li, Shanshan Luo, Jielian Wu & Haihong Fang

  2. Center for Metabolic Disease Research and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

    Margaret Baldini, Dan Shan & Jun Yu

  3. NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine, Jiangxi Institute for Drug Control, Nanchang, 330029, China

    Xupin Liu

  4. Center for Translational Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China

    Yanfei Xie

Authors
  1. Jingyue Yu
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  2. Jinyu Hu
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  4. Huan Lei
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  12. Jun Yu
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Contributions

J-yY performed the experiments, statistical analyses, and wrote the paper draft. J-Yh and Y-fX contributed to network pharmacology analysis. HL and LL performed the animal experiments. J-lW and S-sL contributed to statistical analyses. X-pL and JY supervised the research. MD contributed to correct the draft. H-hF contributed to the design of the study and correct the draft. All the authors approved the final version of the manuscript.

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Correspondence to Haihong Fang.

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Yu, J., Hu, J., Baldini, M. et al. Integrating network pharmacology and experimental models to identify notoginsenoside R1 ameliorates atherosclerosis by inhibiting macrophage NLRP3 inflammasome activation. J Nat Med 78, 644–654 (2024). https://doi.org/10.1007/s11418-023-01776-w

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  • DOI: https://doi.org/10.1007/s11418-023-01776-w

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