Sheng-ji Hua-yu ointment ameliorates cutaneous wound healing in diabetes via up-regulating CCN1

Chronic wounds are typically classified into four subcategories: pressure ulcers, diabetic ulcers (DUs), venous ulceration, and arterial insufficiency ulcers (Mohammedsaeed W et al., 2012). The prevalence of diabetic foot ulcers (DFUs) among people with diabetes is increasing in the United States. It has been reported that 6.5 million patients suffered from DUs in the US alone, which costs more than 200 billion United States Dollar (USD) in healthcare per year (Fotticchia et al., 2015; Verdolino et al., 2021). Therefore, appropriate planning-related interventions to accelerate the healing of diabetic wounds are well warranted.

Traditional Chinese Medicine (TCM) has been increasingly important strategy for treatment of various diseases (Amin et al., 2021; Lozon et al., 2022), such as cardiovascular diseases, tumor, and inflammatory diseases (Abdel-Latif et al., 2022; Dakhly et al., 2020; Hamza et al., 2020). Among them, TCM with conventional treatments received better clinical outcome in treating DUs (Xu et al., 2021; Abdalla et al., 2022). Sheng-ji Hua-yu (SJHY) ointment was formulated under the guidance of the theory of “qu-fu-sheng-xin (eliminating spoilage skin to promote new tissue growth)” (Li, 2000) and “sheng-ji-hua-yu (acceleration of new skin and melting stasis in tissues)” (Li et al., 2011) ground. With herbal formula intervention, the mean time of wound healing is two-three days faster than the usual treatment (cornerstone therapies for external use including Vaseline gauze, mupirocin ointment, and basic fibroblast growth factor (bFGF), which is in accordance with our in vivo experimental results previously (Li et al., 2012). However, the molecular mechanism of SJHY ointment in promoting DU wound healing remains to be further probed.

In light of the inherent complexities of diseases with multitarget, some new approaches such as modular pharmacology that applies multiple-module on the basis of combined treatments have been identified as the novel direction of drug discovery (Yang et al., 2014; Xie et al., 2021; Nelson et al., 2022). ClusterONE (Clustering with Overlapping Neighborhood Expansion) could significantly improve the module detection efficiency, as well as the effect of predicting function modules, considering the topological overlap (Wang et al., 2019; Wang et al., 2012). Currently, in the research of TCM and natural products, modular pharmacology incorporating the ClusterONE implementation has been widely utilized (Kuai et al., 2018). In the meantime, molecular docking is a extensively employed computing technology in new drug development, which is capable of forecasting ligand and target interactions at the molecular level (Pinzi and Rastelli, 2019).

In the present research, we used the ClusterONE algorithm together with modular pharmacology to recognize the biomarkers of the SJHY formula in healing DUs. SJHY ointment exerts therapeutic effects via CCN1 was demonstrated with in vivo and in vitro experimental validation.

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