Diabetic ulcers (DUs) are commonly seen in the lower limbs, especially the feet. Long-term hyperglycaemia in diabetic patients may cause peripheral microvascular damage, which affects local blood flow reconstruction when the skin is ruptured. This results in delayed or even non-healing of skin wounds. Chebulae Fructus Immaturus (CFI) is a traditional Chinese medicine. According to traditional Chinese medicine theory, CFI belongs to the lung channel and large intestine channel. Clinical data confirm a significant clinical effect of CFI in the treatment of skin diseases. CFI can be safely used to treat wounds due to its natural active ingredients. This study utilised HPLC-ESI-QTOF-MS/MS combined with network pharmacology to investigate the mechanism of Chebulae Fructus Immaturus extract (CFIE) in the treatment of DU. Moreover, the efficacy of CFIE on DU was verified in vitro and in vivo by constructing cell models and mouse models. The main ingredients of CFIE were identified by HPLC-ESI-QTOF-MS/MS. The targets of these ingredients were predicted by database analysis and intersected with the DU targets. Gene ontology (GO) was used for functional enrichment of differential genes, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for enrichment of signalling pathways related to the differential genes. The network pharmacology findings were validated in vivo and in vitro, and the affinity of key targets and active components was assessed using molecular docking. Twenty-nine compounds of CFIE were identified by HPLC-ESI-QTOF-MS/MS, and their potential targets were predicted. Among these, 41 targets were associated with DU. KEGG enrichment analysis showed that the PI3K/AKT and HIF-1α signalling pathways were significantly enriched, which may be related to the promotion of wound angiogenesis. In vitro cell experiments showed that CFIE promoted the proliferation, migration and angiogenesis of HUVECs, and also affected the expression of pathway-related proteins. In vivo experiments showed that CFIE increased the expression of pathway-related proteins in wound tissue and promoted the formation of blood vessels. In summary, this study systematically demonstrated the possible therapeutic effects and mechanisms of CFIE on DU through network pharmacology analysis and experimental verification. The results revealed that CFIE can accelerate the angiogenesis of diabetic wounds through the PI3K/AKT and HIF-1α signalling pathways, ultimately promoting the healing of diabetic wounds.

Aliphatic polyester is an important polyester material with good biocompatibility and degradability, which can be synthesized through ring-opening alternating copolymerization (ROAC) of epoxides and anhydrides. Herein, density functional theory (DFT) is used to explore the mechanism of ROAC of epoxides (propylene oxide (PO), styrene oxide (SO), epichlorohydrin (ECH), and cyclohexane oxide (CHO)) and phthalic anhydride (PA) catalyzed by bis(triphenylphosphine) ammonium chloride (PPNCl) and ureas. It was found that the ring-opening polymerization (ROP) of epoxides is the rate-controlling step, and the benzyl alcohol (BnOH) as the initiator has little effect on the polymerization activity, which was consistent with previous experimental results. Calculated comparisons of the ROAC activity of CHO/PA catalyzed by four different ureas indicate that as the Lewis acidity of the urea increased, the energy barriers of the copolymerization increased and the activity decreased. The main reason was that the strong hydrogen-bonding interactions stabilized the key intermediate of the rate-controlling step and inhibited subsequent monomer insertion. Based on this, a series of new ureas with higher catalytic activity were designed by introducing electron-donating substituents. In SO polymerization, increasing the Lewis acidity of urea can improve the SO regioselectivity. In addition, the monomer ECH with CH₂Cl shows higher activity of ROAC than PO and SO, which could be ascribed to the fact that the strong electron-withdrawing Cl atom stabilizes the transition state in the rate-controlling step and reduces the reaction energy barrier.