Key Takeaways & Executive Findings
- ā¢ā¢ Zizhu ointment significantly accelerates wound healing in diabetic ulcer model mice, with faster healing observed at days 3, 7, 11, and 14 compared to model controls. ā¢ Treatment with Zizhu ointment enhances angiogenesis, as evidenced by increased microvessel density and elevated expression of pro-angiogenic factors VEGFA and ANGPT2. ā¢ Zizhu ointment downregulates the expression of angiogenesis inhibitors SPRED1 and PIK3R2, suggesting a mechanism involving the modulation of angiogenic signaling pathways. ā¢ The study provides evidence that topical application of Zizhu ointment may be an effective therapeutic strategy for diabetic ulcers by promoting wound angiogenesis.
Abstract
BACKGROUND: Angiogenesis is one of the critical issues in chronic ulcer healing. Previous studies have indicated that Zizhu ointment can increase the expression of vascular endothelial growth factor in wounds, promote wound healing, and stimulate angiogenesis in high-glucose and high-lipid cell models. OBJECTIVE: To investigate the effects of Zizhu ointment on angiogenesis in diabetic ulcer model mice and elucidate its underlying mechanisms in promoting wound healing. METHODS: Twenty-four mice were randomly divided into four groups: normal control, model control, saline-treated, and Zizhu ointment groups. The diabetic mouse model was established in the latter three groups through a high-fat diet combined with streptozotocin injections. After blood glucose stabilization, full-thickness dorsal skin was removed to simulate diabetic ulcers, with regular monitoring of body mass and blood glucose levels. In the Zizhu ointment group, wound dressings were changed daily. Wound conditions were documented on days 3, 7, 11, and 14. Skin samples were collected after 14 days. Hematoxylin-eosin and Masson staining were used to assess wound healing status. Immunofluorescence staining for vascular endothelial growth factor A (VEGFA) and CD34 was performed to evaluate angiogenesis. Quantitative real-time PCR and western blot analysis were used to detect the expression of angiogenesis-related genes and proteins, including VEGFA, angiopoietin-2 (ANGPT2), sprouty-related EVH1 domain-containing protein 1 (SPRED1), and phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2). RESULTS AND CONCLUSION: The diabetic ulcer model was successfully established. Ulcer healing was delayed in the model group, while the Zizhu ointment group showed significantly faster healing at days 3, 7, 11, and 14 compared with the model group, and at days 7, 11, and 14 compared with the saline group (P < 0.01). Histological staining revealed increased inflammation, reduced hair follicles, and decreased neovascularization in the model group compared with the normal group; the Zizhu ointment group showed increased appendages and neovascularization. Immunofluorescence staining showed reduced positive cells for CD34 and VEGFA in the model group, which were increased after Zizhu ointment treatment. The mean microvessel density in the Zizhu ointment group was higher than that in the model and saline groups (P < 0.05). Gene and protein expression of VEGFA and ANGPT2 were decreased in the model group compared with the normal group (P < 0.01), while SPRED1 and PIK3R2 were significantly increased (P < 0.001). Compared with the model group, the Zizhu ointment group showed significantly increased expression of VEGFA and ANGPT2 (P < 0.05) and decreased expression of SPRED1 and PIK3R2 (P < 0.05), with similar differences compared with the saline group (P < 0.05 or P < 0.01). These findings indicate that streptozotocin-induced diabetic ulcer model mice exhibit delayed ulcer healing and reduced neovascularization. Zizhu ointment treatment accelerates ulcer healing, promotes angiogenesis, and regulates the expression of angiogenesis-related genes and proteins. Thus, topical application of Zizhu ointment may promote diabetic ulcer healing, possibly by modulating wound angiogenesis.
1. Introduction
Diabetic foot ulcers (DFUs) are a severe complication of diabetes mellitus, characterized by impaired wound healing, chronic inflammation, oxidative stress, and vascular dysfunction. Among these, angiogenesisāthe formation of new blood vessels from pre-existing onesāis a critical process for successful wound repair. In DFUs, angiogenesis is often impaired, leading to reduced vascular density and delayed healing. Previous studies have shown that the wound tissue of diabetic patients exhibits decreased vascular surface area, branch points, and total vessel length, along with altered expression of angiogenic factors.
Zizhu ointment, a traditional Chinese medicine preparation from Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, contains six herbal components: Lithospermum erythrorhizon, cinnabar, borneol, Astragalus membranaceus, dragon's blood, and donkey-hide gelatin. Our preliminary research demonstrated that Zizhu ointment can increase the expression of vascular endothelial growth factor (VEGF) in wounds and promote healing, as well as stimulate angiogenesis in high-glucose and high-lipid cell models. However, the underlying mechanisms remain unclear.
This study aims to investigate the effects of Zizhu ointment on angiogenesis in a diabetic ulcer mouse model and to explore the molecular mechanisms by which it promotes wound healing. We focused on key angiogenic regulators, including VEGFA, angiopoietin-2 (ANGPT2), sprouty-related EVH1 domain-containing protein 1 (SPRED1), and phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), which are known to play crucial roles in the angiogenic process.
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Li Wenhui, Shi Chenyan, Yang Yiyan, Liu Guobin (2026). Zizhu ointment enhances wound healing in diabetic ulcer mice via angiogenesis regulation. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21580
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Frequently Asked Questions
What is the effect of Zizhu ointment on diabetic ulcer healing?
Zizhu ointment significantly accelerates wound healing in diabetic ulcer model mice, as demonstrated by faster closure rates at days 3, 7, 11, and 14 compared to untreated controls.
How does Zizhu ointment promote angiogenesis in diabetic ulcers?
Zizhu ointment promotes angiogenesis by increasing the expression of pro-angiogenic factors such as vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2), while decreasing the expression of angiogenesis inhibitors like SPRED1 and PIK3R2.
What are the key molecular targets of Zizhu ointment in wound healing?
The key molecular targets include VEGFA, ANGPT2, SPRED1, and PIK3R2, which are involved in the regulation of angiogenesis. Zizhu ointment modulates their expression to enhance neovascularization.
What is the significance of this study for diabetic ulcer treatment?
This study provides evidence that Zizhu ointment, a traditional Chinese medicine, can effectively promote diabetic ulcer healing by modulating angiogenesis, suggesting its potential as a therapeutic agent for diabetic foot ulcers.
What animal model was used in this study?
A diabetic ulcer mouse model was established using a high-fat diet combined with streptozotocin injections, which mimics type 2 diabetes and results in impaired wound healing.
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