Intragastric administration of Pien Tze Huang enhanced wound healing in diabetes by inhibiting inflammation and improving energy generation.

ABSTRACT

BACKGROUND AND PURPOSE: As a complex and challenging complication for the patients with diabetes mellitus, diabetic ulcers are difficult to heal and current strategies cannot fulfill the patients' requirements. Pien Tze Huang (PZH) is a standardized medicine approved for various wounds treatments, and this study systematically investigated the effect and mechanism of intragastric administration of PZH (I-PZH) on diabetic wound healing. METHODS AND RESULTS: The effect of I-PZH on the healing of full-thickness wounds in rats with diabetes mellitus which was induced by high fat diet followed by streptozotocin injection was evaluated, and RNA sequencing (RNA-seq) and targeted central carbon metabolism metabolomics were combined to explore the underlying mechanism. I-PZH promoted wound healing, facilitated extracellular matrix synthesis, and maintained body weight of rats, but did not affect fasting blood glucose levels. Additionally, I-PZH significantly decreased 8-OHdG, cleaved caspase 3 and MMP9 levels, and increased TGF-ß1 expression. RNA-seq analysis showed that I-PZH inhibited inflammation and that the vital common targets were TLR2, IL-17A and IL-1ß; specifically affected "energy derivation by oxidation of organic compounds" with UQCRC1, NDUFS3 and SDHA as vital specific targets. Further experiments confirmed that I-PZH reduced TLR2, IL-17A and IL-1ß, increased UQCRC1, SDHA, NDUFS3, promoted ATP synthesis and restored activity of mitochondrial respiratory chain complexes I and III in diabetic wounds. Metabolomics by HPLC-MS/MS analysis showed that I-PZH reversed multiple energy metabolism-related metabolites such as glucuronic acid, GMP, d-gluconic acid, cis-aconitic acid, ribose 5-phosphate and pantothenate. CONCLUSION: This study highlights the important role of inflammation and energy generation in diabetic wound healing, reveals wound repair mechanism of PZH and promotes its clinical application in diabetic wound treatment.