Abstract：
BACKGROUND: Chronic diabetic wounds pose a significant threat to the health of diabetic patients, representing severe and enduring complications. Globally, an estimated 2.5% to 15% of the annual health budget is associated with diabetes, with diabetic wounds accounting for a substantial share. Exploring new therapeutic agents and approaches to address delayed and impaired wound healing in diabetes becomes imperative. Traditional Chinese medicine (TCM) has a long history and remarkable efficacy in treating chronic wound healing. In this study, all topically applied proprietary Chinese medicines (pCMs) for wound healing officially approved by the National Medical Products Administration (NMPA) were collected from the NMPA TCM database. Data mining was employed to obtain a high-frequency TCM ingredients pair, Pearl-Borneol (1:1).
METHODS: This study investigated the effect and molecular mechanism of the Pearl-Borneol pair on the healing of diabetic wounds by animal experiments and metabolomics. The results from animal experiments showed that the Pearl-Borneol pair significantly accelerated diabetic wound healing, exhibiting a more potent effect than the Pearl or Borneol treatment alone. Meanwhile, the metabolomics analysis identified significant differences in metabolic profiles in wounds between the model and normal groups, indicating that diabetic wounds had distinct metabolic characteristics from normal wounds. Moreover, Vaseline-treated wounds exhibited similar metabolic profiles to the wounds from the model group, suggesting that Vaseline might have a negligible impact on diabetic wound metabolism. In addition, wounds treated with Pearl, Borneol, and Pearl-Borneol pair displayed significantly different metabolic profiles from Vaseline-treated wounds, signifying the influence of these treatments on wound metabolism. Subsequent enrichment analysis of the metabolic pathway highlighted the involvement of the arginine metabolic pathway, closely associated with diabetic wounds, in the healing process under Pearl- Borneol pair treatment. Further analysis revealed elevated levels of arginine and citrulline, coupled with reduced nitric oxide (NO) in both the model and Vaseline-treated wounds compared to normal wounds, pointing to impaired arginine utilization in diabetic wounds. Interestingly, treatment with Pearl and Pearl-Borneol pair lowered arginine and citrulline levels while increasing NO content, suggesting that these treatments may promote the catabolism of arginine to generate NO, thereby facilitating faster wound closure. Additionally, borneol alone significantly elevated NO content in wounds, potentially due to its ability to directly reduce nitrates/nitrites to NO. Oxidative stress is a defining characteristic of impaired metabolism in diabetic wounds.
RESULTS: The result showed that both Pearl and Pearl-Borneol pair decreased the oxidative stress biomarker methionine sulfoxide level in diabetic wounds compared to those treated with Vaseline, indicating that Pearl alone or combined with Borneol may enhance the oxidative stress microenvironment in diabetic wounds.
CONCLUSIONS: In summary, the findings validate the effectiveness of the Pearl-Borneol pair in accelerating the healing of diabetic wounds, with effects on reducing oxidative stress, enhancing arginine metabolism, and increasing NO generation, providing a mechanistic basis for this therapeutic approach.
METHODS: This study investigated the effect and molecular mechanism of the Pearl-Borneol pair on the healing of diabetic wounds by animal experiments and metabolomics. The results from animal experiments showed that the Pearl-Borneol pair significantly accelerated diabetic wound healing, exhibiting a more potent effect than the Pearl or Borneol treatment alone. Meanwhile, the metabolomics analysis identified significant differences in metabolic profiles in wounds between the model and normal groups, indicating that diabetic wounds had distinct metabolic characteristics from normal wounds. Moreover, Vaseline-treated wounds exhibited similar metabolic profiles to the wounds from the model group, suggesting that Vaseline might have a negligible impact on diabetic wound metabolism. In addition, wounds treated with Pearl, Borneol, and Pearl-Borneol pair displayed significantly different metabolic profiles from Vaseline-treated wounds, signifying the influence of these treatments on wound metabolism. Subsequent enrichment analysis of the metabolic pathway highlighted the involvement of the arginine metabolic pathway, closely associated with diabetic wounds, in the healing process under Pearl- Borneol pair treatment. Further analysis revealed elevated levels of arginine and citrulline, coupled with reduced nitric oxide (NO) in both the model and Vaseline-treated wounds compared to normal wounds, pointing to impaired arginine utilization in diabetic wounds. Interestingly, treatment with Pearl and Pearl-Borneol pair lowered arginine and citrulline levels while increasing NO content, suggesting that these treatments may promote the catabolism of arginine to generate NO, thereby facilitating faster wound closure. Additionally, borneol alone significantly elevated NO content in wounds, potentially due to its ability to directly reduce nitrates/nitrites to NO. Oxidative stress is a defining characteristic of impaired metabolism in diabetic wounds.
RESULTS: The result showed that both Pearl and Pearl-Borneol pair decreased the oxidative stress biomarker methionine sulfoxide level in diabetic wounds compared to those treated with Vaseline, indicating that Pearl alone or combined with Borneol may enhance the oxidative stress microenvironment in diabetic wounds.
CONCLUSIONS: In summary, the findings validate the effectiveness of the Pearl-Borneol pair in accelerating the healing of diabetic wounds, with effects on reducing oxidative stress, enhancing arginine metabolism, and increasing NO generation, providing a mechanistic basis for this therapeutic approach.
摘要：
背景：慢性糖尿病伤口对糖尿病患者的健康构成重大威胁，代表严重和持久的并发症。全球范围内,估计有2.5%到15%的年度健康预算与糖尿病有关，糖尿病伤口占很大比例。探索新的治疗剂和方法来解决糖尿病中延迟和受损的伤口愈合变得势在必行。中药治疗慢性创面愈合历史悠久,疗效显著。在这项研究中,所有经国家药品监督管理局（NMPA）正式批准的局部应用的伤口愈合中成药（pCM）均来自NMPATCM数据库。采用数据挖掘的方法获得了一个高频中药成分对,珍珠冰片（1：1）。
方法：本研究通过动物实验和代谢组学研究了珍珠-冰片对糖尿病创面愈合的影响和分子机制。动物实验结果显示,珍珠-冰片对显著加速糖尿病创面愈合,表现出比单独的珍珠或冰片治疗更有效的效果。同时,代谢组学分析确定了模型组和正常组之间伤口代谢谱的显着差异，表明糖尿病伤口具有与正常伤口不同的代谢特征。此外，凡士林处理的伤口表现出与模型组伤口相似的代谢特征，这表明凡士林对糖尿病伤口代谢的影响可以忽略不计。此外,用珍珠治疗的伤口,冰片,和珍珠-冰片对显示出与凡士林治疗伤口明显不同的代谢谱，表示这些治疗对伤口代谢的影响。随后对代谢途径的富集分析强调了精氨酸代谢途径的参与，与糖尿病伤口密切相关，在珍珠-冰片对治疗的愈合过程中。进一步分析显示精氨酸和瓜氨酸水平升高，与正常伤口相比，模型伤口和凡士林处理伤口中的一氧化氮（NO）减少，指出糖尿病伤口中精氨酸的利用受损。有趣的是,用珍珠和珍珠-冰片对治疗降低精氨酸和瓜氨酸水平，同时增加NO含量，提示这些治疗可能促进精氨酸的分解代谢产生NO，从而促进更快的伤口闭合。此外,单独冰片显著升高伤口中的NO含量，可能是由于其直接将硝酸盐/亚硝酸盐还原为NO的能力。氧化应激是糖尿病伤口中代谢受损的决定性特征。
结果：结果表明，与凡士林治疗相比，Pearl和Pearl-Borneol对降低了糖尿病伤口中氧化应激生物标志物甲硫氨酸亚砜的水平，表明Pearl单独或联合冰片可增强糖尿病伤口的氧化应激微环境。
结论：总之，研究结果验证了珍珠冰片对加速糖尿病伤口愈合的有效性，具有减少氧化应激的作用，增强精氨酸代谢，增加NO的产生，为这种治疗方法提供了机械基础。
方法：本研究通过动物实验和代谢组学研究了珍珠-冰片对糖尿病创面愈合的影响和分子机制。动物实验结果显示,珍珠-冰片对显著加速糖尿病创面愈合,表现出比单独的珍珠或冰片治疗更有效的效果。同时,代谢组学分析确定了模型组和正常组之间伤口代谢谱的显着差异，表明糖尿病伤口具有与正常伤口不同的代谢特征。此外，凡士林处理的伤口表现出与模型组伤口相似的代谢特征，这表明凡士林对糖尿病伤口代谢的影响可以忽略不计。此外,用珍珠治疗的伤口,冰片,和珍珠-冰片对显示出与凡士林治疗伤口明显不同的代谢谱，表示这些治疗对伤口代谢的影响。随后对代谢途径的富集分析强调了精氨酸代谢途径的参与，与糖尿病伤口密切相关，在珍珠-冰片对治疗的愈合过程中。进一步分析显示精氨酸和瓜氨酸水平升高，与正常伤口相比，模型伤口和凡士林处理伤口中的一氧化氮（NO）减少，指出糖尿病伤口中精氨酸的利用受损。有趣的是,用珍珠和珍珠-冰片对治疗降低精氨酸和瓜氨酸水平，同时增加NO含量，提示这些治疗可能促进精氨酸的分解代谢产生NO，从而促进更快的伤口闭合。此外,单独冰片显著升高伤口中的NO含量，可能是由于其直接将硝酸盐/亚硝酸盐还原为NO的能力。氧化应激是糖尿病伤口中代谢受损的决定性特征。
结果：结果表明，与凡士林治疗相比，Pearl和Pearl-Borneol对降低了糖尿病伤口中氧化应激生物标志物甲硫氨酸亚砜的水平，表明Pearl单独或联合冰片可增强糖尿病伤口的氧化应激微环境。
结论：总之，研究结果验证了珍珠冰片对加速糖尿病伤口愈合的有效性，具有减少氧化应激的作用，增强精氨酸代谢，增加NO的产生，为这种治疗方法提供了机械基础。
