Novel monomers recipe derived from Shengji-Huayu formula targeting PI3K/Akt signaling pathway for diabetic wound healing based on accurate network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE

Shengji-Huayu (SJHY) formula has been used clinically for diabetic ulcer (DU) treatment. The transcriptional profiles analysis revealed the PI3K/Akt signaling pathway plays a critical role for diabetic wound healing. However, the effects and underlying mechanisms of SJHY are often challenging in diabetic wound treatment.

AIM OF THE STUDY

To explore the novel monomers recipe and mechanism of SJHY treated diabetic wound via the in vivo and in vitro experiments.

MATERIALS AND METHODS

The diabetic wound mice model was established to evaluate the therapeutic efficacy of SJHY treated diabetic ulcer. The transcriptional profile was implemented to identify the differentially expressed genes (DEGs) of SJHY treated diabetic wound mice. The constructed PPI network and KEGG-target network were used to identify the core pathway and related targets. The HPLC-MS method was used to identify the ingredients of SJHY formula. The molecular docking and in vitro experiment was used to screen which monomers regulated core pathway in diabetic wound. Finally, a novel monomers recipe was performed for diabetic wound healing.

RESULTS

The in vivo experiment demonstrated SJHY formula significantly promoted diabetic wound healing. Transcriptomic and network analysis revealed the existence of PI3K/Akt signaling pathway was high correlated with SJHY treated diabetic wound. The HPLC-MS and molecular docking revealed that Calycosin (Cal) and Dehydromiltirone (DHT) were strongly targeting Itga6 and Thbs1. The mRNA and protein levels suggested that Itga6 and Thbs1 acted as important upstream regulators of PI3K/Akt signaling pathway in diabetic wound, and the in vitro experiments revealed Cal, DHT and their recipe were significantly increased the levels of Itga6, Thbs1, PI3K and Akt in MGO induced HaCaT cells.

CONCLUSIONS

SJHY formula has therapeutic efficiency for diabetic wound healing, and Cal and DHT may be a part of the important monomers that alleviate inflammation via activating the PI3K/Akt signaling pathway by regulated Itga6 and Thbs1. Our study demonstrated Cal and DHT formed a novel monomers recipe, which may be one of the critical strategies of SJHY formula promote diabetic wound healing.