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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
X-Paste improves wound healing in diabetes via NF-E2-related factor/HO-1 signaling pathway
Ming-Wei Du, Xin-Lin Zhu, Dong-Xing Zhang, Xian-Zhen Chen, Li-Hua Yang, Jin-Zhou Xiao, Wen-Jie Fang, Xiao-Chun Xue, Wei-Hua Pan, Wan-Qing Liao, Tao Yang
Ming-Wei Du, Tao Yang, Institute of Cardiovascular Disease, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, China
Ming-Wei Du, Xin-Lin Zhu, Xian-Zhen Chen, Jin-Zhou Xiao, Wen-Jie Fang, Xiao-Chun Xue, Wei-Hua Pan, Wan-Qing Liao, Department of Dermatology, Shanghai Key Laboratory of Molecular Medical Mycology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China
Dong-Xing Zhang, Department of Dermatology, Dongshan Hospital, Meizhou 514000, Guangdong Province, China
Xian-Zhen Chen, Department of Dermatology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, Shandong Province, China
Li-Hua Yang, Department of Emergency, Naval Hospital of Eastern Theater, Zhoushan 316000, Zhejiang Province, China
Xiao-Chun Xue, Department of Pharmacy, 905th Hospital of People’s Liberation Army of China (PLA) Navy, Shanghai 200052, China
Co-first authors: Ming-Wei Du and Xin-Lin Zhu.
Co-corresponding authors: Wan-Qing Liao and Tao Yang.
Author contributions: Yang T, Liao WQ, and Pan WH conceived the experiments and be responsible in the vital revision of manuscript; Du MW, Zhu XL, and Zhang DX contributed to carry out experiments including Western blotting, IF, and so on; Chen XZ, Yang LH, Xiao JZ, and Fang WJ drafted of the manuscript; Xue XC interpreted and analyzed data; Du MW and Zhu XL made the same contribution to this work and should share the first authorship; Liao WQ and Yang T should share the corresponding authorship since they contributed efforts of equal substance throughout the research process; and all authors have read and approved the final version of the manuscript.
Supported by the Shanghai Science and Technology Innovation Project, One Belt One Road International Joint Laboratory of Medical Mycology, No. 21410750500.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Review Board of Second Affiliated Hospital of Naval Medical University (Approval No. 2020YCGPZ-102).
Conflict-of-interest statement: The authors have declared that no competing interest exists.
Data sharing statement: All data are provided in this study, and raw data can be requested to the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Tao Yang, PhD, Associate Professor, Institute of Cardiovascular Disease, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Pudong New Area, Shanghai 200120, China. yangtao@shutcm.edu.cn
Received: December 17, 2023
Revised: January 31, 2024
Accepted: March 25, 2024
Published online: June 15, 2024
BACKGROUND
Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality.
AIM
To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice.
METHODS
Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP’s main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP’s treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro’s molecular mechanisms.
RESULTS
XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro’s proliferative and endothelial protective effects.
CONCLUSION
XP significantly promotes wound healing in STZ-induced diabetic models. As XP’s key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.
Core Tip: Diabetic foot ulcer (DFU) is a severe complication caused by diabetes mellitus. The healing process and time of skin wounds in diabetic mice are visibly improved by the application of X-Paste (XP). The analysis conducted on XP unveiled its 21 main components, with Andrographolide (Andro) displaying a notable binding ability with NF-E2-related factor-2 (Nrf2) by high-performance liquid chromatography. Moreover, the addition of Andro at the cellular level effectively alleviated high glucose (HG)-induced proliferation, migration, vascular injury, and inhibition of inflammatory products in human umbilical vein endothelial cells (HUVECs). Mechanistically, the Nrf2/HO-1 signaling pathway is activated by Andro, leading to the relief of HG-induced damage to HUVECs.
