Wei WH, Bai YL, Zhu D, Zhang JY, Yin QC, Li Q, Shen CQ, Jin PS. Dl-3-n-butylphthalide ameliorates diabetic foot ulcer by inhibiting apoptosis and promoting angiogenesis. World J Diabetes 2025; 16(4): 101916 [DOI: 10.4239/wjd.v16.i4.101916]
Corresponding Author of This Article
Pei-Sheng Jin, MD, Professor, Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, No. 84 Huaihai West Road, Quanshan District, Xuzhou 221006, Jiangsu Province, China. peishengjin@xzhmu.edu.cn
Research Domain of This Article
Medicine, Research & Experimental
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Wu-Han Wei, Yuan-Ling Bai, Dong Zhu, Jing-Yu Zhang, The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
Wu-Han Wei, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100144, China
Yuan-Ling Bai, Dong Zhu, Jing-Yu Zhang, Qi-Chuan Yin, Qiang Li, Cai-Qi Shen, Pei-Sheng Jin, Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
Co-first authors: Wu-Han Wei and Yuan-Ling Bai.
Co-corresponding authors: Cai-Qi Shen and Pei-Sheng Jin.
Author contributions: Wei WH and Bai YL performed the research, acquired the data, and drafted the manuscript, they contributed equally as co-first authors; Zhu D, Zhang JY, and Yin QC analyzed and evaluated the data; Shen CQ contributed to the pharmacological analysis; Shen CQ, Jin PS, and Li Q contributed to the conception of the study and reviewed the manuscript; Jin PS and Shen CQ made essential contributions to the supervision of the research, they contributed equally as co-corresponding authors; and all authors approved the final version.
Supported by General Project of Xuzhou Science and Technology Bureau, No. KC22070.
Institutional animal care and use committee statement: All experimental protocols followed the guidelines of animal experimentation and were approved by the Experimental Animal Administrative Committee of Xuzhou Medical University (Approval No. 202311T023).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Pei-Sheng Jin, MD, Professor, Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, No. 84 Huaihai West Road, Quanshan District, Xuzhou 221006, Jiangsu Province, China. peishengjin@xzhmu.edu.cn
Received: October 1, 2024 Revised: December 10, 2024 Accepted: January 21, 2025 Published online: April 15, 2025 Processing time: 150 Days and 7.4 Hours
Abstract
BACKGROUND
Diabetic foot ulcers (DFU) are estimated to affect about 18.6 million people worldwide annually. The pathogenesis of DFU is complex, and the available drugs are not effective. Dl-3-n-butylphthalide (NBP) is a synthetic mixture of racemates used in China for the treatment of ischemic stroke. It was initially isolated from the seeds of Apium graveolens Linn, with studies showing its potential role in treating diabetes and its complications.
AIM
To predict and validate the mechanism by which NBP treats DFU.
METHODS
Network pharmacological analysis was performed to identify pharmacological targets and signaling pathways mediating the treatment effect of NBP on DFU. In vivo and in vitro experiments were conducted to validate the therapeutic effects and mechanisms of NBP on DFU.
RESULTS
Network pharmacology analysis identified 26 pharmacological targets of NBP and predicted that NBP could treat DFU partially by modulating apoptosis and vascular signaling pathways. Results from animal experiments showed that NBP significantly improved DFU by increasing neovascularization and fibroblast proliferation. In vitro tests demonstrated that NBP treatment promoted the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts, while inhibiting the apoptosis of human umbilical vein endothelial cells, human dermal fibroblasts, and human keratinocytes cells.
CONCLUSION
This study found that NBP could treat DFU by decreasing the rate of apoptosis and increasing angiogenesis via the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to the heme oxygenase 1, caspase 3, B cell leukemia/lymphoma 2, brain derived neurotrophic factor, and nuclear factor erythroid 2 L2 genes.
Core Tip: Network pharmacology analysis demonstrated that Dl-3-n-butylphthalide (NBP) could treat diabetic foot ulcers (DFU) by modulating apoptosis and vascular signaling pathways. Moreover, improved neovascularization in DFU mice and enhanced the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts, while inhibiting apoptosis of human umbilical vein endothelial cells, human dermal fibroblasts, and human keratinocytes cells. The effects of NBP were mediated by activation of the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to heme oxygenase 1, caspase 3, B cell leukemia/lymphoma 2, brain derived neurotrophic factor, and nuclear factor erythroid 2 L2, suggesting that NBP can potentially treat DFU by reducing apoptosis and promoting angiogenesis.
