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Protective mechanisms of loquat leaf extract and ursolic acid against diabetic pro-inflammation

Abstract

The pharmacological effectiveness of loquat leaf extract (LE) and its important component, ursolic acid (UA), in the treatment of diabetes mellitus, has been well established in traditional medicine; however, the mechanism underlying their action is still unclear. We evaluated the protective effects of LE and UA against hyperglycemia-induced advanced glycation end product (AGE) formations and hepatic pro-inflammation. Oral administration of UA and LE at a dose of 50 mg/kg/day for 15 days yielded no significant hypoglycemic effect in diabetic db/db mice. UA and LE suppressed hepatic oxidative stress and AGE formation in diabetic mice, and this was followed by the downregulated mitogen-activated protein kinase signaling and nuclear factor κ B (NF-κB) activity. To identify the molecular target of LE and UA, a docking simulation was performed, and this predicted UA to bind to liver kinase B1 (LKB1), an upstream of AMP-activated protein kinase (AMPK)/transcription factor forkhead box O3 (FOXO3) axis. UA reversed the high-glucose-induced downregulation of LKB1-AMPK1-FOXO3 activation and antioxidant gene transcription. These findings demonstrated the antioxidant and anti-inflammatory effects of UA and LE against hyperglycemia-induced hepatic inflammation. Furthermore, we speculate that the LKB1/AMPK/FOXO3 pathway is a potential target responsible for these beneficial effects of LE and UA.

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Acknowledgements

We thank the Aging Tissue Bank (NRF-2015M3A9B8029074) for supplying research materials for this study.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (2018R1A2A3075425 and 2019R1F1A1057138).

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Authors and Affiliations

Authors

Contributions

MKH, DHK, YJC, and HYC designed the study and analyzed the data. MKH, DHK, CHP, SGN, SC, JYL, JHC, and DP performed experiments. The first draft of the manuscript was written by MKH and YJC and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yeon Ja Choi or Hae Young Chung.

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Ethics approval

The animal study was approved by the Pusan National University-Institutional Animal Care and Use Committee (PNU-IACUC) for ethical procedures and scientific care (Approval Number PNU-2019–2231).

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The authors declare no competing interests.

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Key messages

• Short-term oral administration of LE and UA had no significant hypoglycemic effect.

• UA and LE suppressed oxidative stress, AGE formation, and pro-inflammatory signaling in diabetic mice.

• LKB1 was found as a potential target of UA.

• UA induced LKB1-AMPK1-FOXO3 activation and antioxidant gene transcription.

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Hyun, M.K., Kim, D.H., Park, C.H. et al. Protective mechanisms of loquat leaf extract and ursolic acid against diabetic pro-inflammation. J Mol Med 100, 1455–1464 (2022). https://doi.org/10.1007/s00109-022-02243-x

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  • DOI: https://doi.org/10.1007/s00109-022-02243-x

Keywords

  • AGEs
  • Diabetes
  • FOXO3
  • LKB1
  • Loquat
  • Ursolic acid