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Lonicerin promotes wound healing in diabetic rats by enhancing blood vessel regeneration through Sirt1-mediated autophagy

Acta Pharmacologica Sinica volume 45, pages 815–830 (2024)Cite this article

Abstract

Among the numerous complications of diabetes mellitus, diabetic wounds seriously affect patients’ quality of life and result in considerable psychological distress. Promoting blood vessel regeneration in wounds is a crucial step in wound healing. Lonicerin (LCR), a bioactive compound found in plants of the Lonicera japonica species and other honeysuckle plants, exhibits anti-inflammatory and antioxidant activities, and it recently has been found to alleviate ulcerative colitis by enhancing autophagy. In this study we investigated the efficacy of LCR in treatment of diabetic wounds and the underlying mechanisms. By comparing the single-cell transcriptomic data from healing and non-healing states in diabetic foot ulcers (DFU) of 5 patients, we found that autophagy and SIRT signaling activation played a crucial role in mitigating inflammation and oxidative stress, and promoting cell survival in wound healing processes. In TBHP-treated human umbilical vein endothelial cells (HUVECs), we showed that LCR alleviated cell apoptosis, and enhanced the cell viability, migration and angiogenesis. Furthermore, we demonstrated that LCR treatment dose-dependently promoted autophagy in TBHP-treated HUVECs by upregulating Sirt1 expression, and exerted its anti-apoptotic effect through the Sirt1-autophagy axis. Knockdown of Sirt1 significantly decreased the level of autophagy, and mitigated the anti-apoptotic effect of LCR. In a STZ-induced diabetic rat model, administration of LCR significantly promoted wound healing, which was significantly attenuated by Sirt1 knockdown. This study highlights the potential of LCR as a therapeutic agent for the treatment of diabetic wounds and provides insights into the molecular mechanisms underlying its effects.

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Fig. 1: Lonicerin treatment decreases TBHP-induced apoptosis in HUVECs.
Fig. 2: Lonicerin combats TBHP-induced apoptosis and promotes the function of HUVECs.
Fig. 3: Lonicerin promotes autophagy in TBHP-treated HUVECs.
Fig. 4: Lonicerin promotes autophagy by increasing Sirt1 expression.
Fig. 5: Anti-apoptotic effects of Lonicerin (LCR) are related to Sirt1 in HUVECs.
Fig. 6: Lonicerin accelerates cutaneous wound healing in rats.
Fig. 7: Lonicerin accelerates cutaneous wound healing in rats (continue).
Fig. 8

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The Single cell RNA-seq data were obtained in the NCBI GEO: https://ncbi.nlm.nih.gov/geo/ under accession numbers GSE165816.

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Acknowledgements

This study is funded by the National Natural Science Foundation of China (82202468, 82372532), Natural Science Foundation of Guangdong Province (2023A1515012227), the Foundation of Guangzhou Municipal Science and Technology Bureau, the Basic Research Program - Basic and Applied Basic Research Project (2023A04J2355), High Level Introduction of Talent Research Startup Fund Southern Medical University (Gaofeng Wang) and Nanfang Hospital Distinguished Young Cultivation Program (2022J003).

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Authors and Affiliations

  1. Department of Plastic and Aesthetic Surgery, Nanfang Hospital of Southern Medical University, Guangzhou, 510515, China

    Zhen Lin, Lu Chen, Yue Li, Lan Yang, Chang-zhou Li, Cai-yu Qi, Yu-yang Gan, Jia-rui Zhang, Piao Wang & Gao-feng Wang

  2. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21210, USA

    Zhen Lin & Gao-feng Wang

  3. College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea

    Lu-yao Li

  4. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, 325702, China

    Chen Jin

  5. Department of Orthopaedic Surgery, Zhejiang Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, 310014, China

    Li-bin Ni

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Contributions

ZL and LYL performed experiments, drafted and critically revised the manuscript. ZL, CJ, JRZ, CYQ and PW analyzed, interpreted the data and critically revised the manuscript. LY, CZL, YYG, LC, YL and LBN performed statistical analysis. LBN and GFW conceived, designed the study, discussed the experiments and critically revised the manuscript. All authors have approved the final manuscript and have agreed to be accountable for all the aspects of the work.

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Correspondence to Li-bin Ni or Gao-feng Wang.

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Lin, Z., Li, Ly., Chen, L. et al. Lonicerin promotes wound healing in diabetic rats by enhancing blood vessel regeneration through Sirt1-mediated autophagy. Acta Pharmacol Sin 45, 815–830 (2024). https://doi.org/10.1038/s41401-023-01193-5

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