Integrating Data Mining with Metabolomics to Analyze the Mechanism of the "Pearl-Borneol" Pair in Promoting Healing of Diabetic Wounds
Authors: Deng Yasheng , Luo Xuefei , Lai Weihui , Jiang Chunhui , Zheng Yingwen , Pi Zhenyu , Yang Yingyi , Li Jinhua , Zhang Ningle , Luo Xiaolin , Tong Yuanming , Liu Peng , Luo Fei , Lin Jiang , Lan Taijin 
Published: July 2024

Introduction:
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 to 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.

Methods:
In this study, all topically applied Proprietary Chinese Medicines (pCMs) for wound
healing officially approved by China National Medical Products Administration (NMPA) were
collected from the NMPA TCM database. Data mining was employed to obtain a highfrequency
TCM ingredients pair, Pearl-Borneol (1:1). Subsequently, This study investigated the
effect and molecular mechanism of the Pearl-Borneol pair on the healing of diabetic wounds by
animal experiments and metabolomics.

Results:
The 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. Our 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.

Conclusion:
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.