Cen LS, Cao Y, Zhou YM, Guo J, Xue JW. Shikonin protects mitochondria through the NFAT5/AMPK pathway for the treatment of diabetic wounds. World J Diabetes 2024; 15(12): 2338-2352 [PMID: 39676806 DOI: 10.4239/wjd.v15.i12.2338]
Corresponding Author of This Article
Lu-Sha Cen, PhD, Attending Doctor, Department of Ophthalmology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), No. 54 Youdian Road, Hangzhou 310006, Zhejiang Province, China. cenlusa2@sina.com
Research Domain of This Article
Dermatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Dec 15, 2024; 15(12): 2338-2352 Published online Dec 15, 2024. doi: 10.4239/wjd.v15.i12.2338
Shikonin protects mitochondria through the NFAT5/AMPK pathway for the treatment of diabetic wounds
Lu-Sha Cen, Yi Cao, Yi-Mai Zhou, Jing Guo, Jing-Wen Xue
Lu-Sha Cen, Department of Ophthalmology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, Zhejiang Province, China
Yi Cao, Jing Guo, Department of Dermatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, Zhejiang Province, China
Yi-Mai Zhou, The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
Jing-Wen Xue, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou 310023, Zhejiang Province, China
Author contributions: Cen LS participated in study design, drafted the manuscript, and performed data analysis; Zhou YM assisted with the original draft preparation; Guo J and Xue JW participated in data analysis; Cao Y was involved in study design and data curation and supervised the study. All authors have read and approved the final version of the manuscript.
Supported byNational Natural Science Foundation of China, No. 82104862; Zhejiang Provincial Natural Science Foundation of China, No. LTY22E030003; and Scientific Research Project Foundation of Zhejiang Chinese Medical University, No. 2023FSYYZZ01.
Institutional animal care and use committee statement: According to the audit of the laboratory animal management and ethics committee, the animal experiment process of this project conforms to the principles of the animal protection, the animal welfare and the ethics as well as the related stipulation on national experimental animal welfare ethics. All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Zhejiang Chinese Medical University Animal Center.
Conflict-of-interest statement: No potential conflict of interest was reported by the authors.
Data sharing statement: The data used to support the findings of this study are included within the article.
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: Lu-Sha Cen, PhD, Attending Doctor, Department of Ophthalmology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), No. 54 Youdian Road, Hangzhou 310006, Zhejiang Province, China. cenlusa2@sina.com
Received: March 17, 2024 Revised: August 28, 2024 Accepted: October 10, 2024 Published online: December 15, 2024 Processing time: 246 Days and 1 Hours
Abstract
BACKGROUND
Shikonin is a natural remedy that is effective at treating diabetic wounds. NFAT5 is a potential therapeutic target for diabetes, and mitochondrial function is essential for wound healing. However, the relationship among Shikonin, NFAT5, and mitochondrial function has not been thoroughly studied. Here, we offer new perspectives on the advantages of shikonin for managing diabetes.
AIM
To assess the therapeutic mechanism of shikonin in diabetic wounds, its relationship with NFAT5, and its protection of mitochondrial function.
METHODS
Hypertonic cell and diabetic wound mouse models were established. NFAT5 expression was measured through western blotting and immunofluorescence, in vivo and in vitro. Mitochondrial function was evaluated using reactive oxygen species (ROS) detection and JC-1 and Calcein AM dyes. Mitochondrial structures were observed using transmission electron microscopy. The NFAT5/AMPK pathway was analyzed using a transfection vector and an inhibitor. The effect of shikonin on cells under hypertonic conditions via the NFAT5/AMPK pathway was assessed using western blotting.
RESULTS
Shikonin treatment preserved HaCaT cell viability, while significantly reducing cyclooxygenase-2 expression levels in a high-glucose environment (P < 0.05). Additionally, shikonin maintained mitochondrial morphology, enhanced membrane potential, reduced membrane permeability, and decreased ROS levels in HaCaT cells under hyperosmolar stress. Furthermore, shikonin promoted wound healing in diabetic mice (P < 0.05). Shikonin also inhibited NFAT5, in vivo and in vitro (P < 0.05). Shikonin treatment reduced NFAT5 expression levels, subsequently inhibiting AMPK expression in vitro (P < 0.05). Finally, shikonin inhibited several key downstream molecules of the NFAT5/AMPK pathway, including mammalian target of rapamycin, protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and inducible nitric oxide synthase (P < 0.05).
CONCLUSION
Shikonin protects mitochondria via the NFAT5/AMPK-related pathway and enhances wound healing in diabetes.
Core Tip: NFAT5 is a potential therapeutic target for diabetes. Shikonin is a natural remedy that is ideal for treating diabetic wounds. In this study we confirmed that shikonin suppresses the pathological expression of NFAT5, thereby protecting mitochondrial function, inhibiting cellular inflammation, and reducing reactive oxygen species production. Furthermore, we found that shikonin protects mitochondria through the NFAT5/AMPK pathway. Our research provides novel insights into the contribution of shikonin to the treatment of diabetes.
