Dl-3-n-butylphthalide ameliorates diabetic foot ulcer by inhibiting apoptosis and promoting angiogenesis.

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.