Fang Zhang1,2, Ye Liu2 , Shiqi Wang1 , Xin Yan1 , Yue Lin1 , Deyan Chen2*, Qian Tan1* and Zhiwei Wu2,3,4*

1 Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China, 2 Center for Public Health Research, Medical School, Nanjing University, Nanjing, China, 3 State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China, 4 Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, China.

       Diabetic foot ulcer (DFU) frequently leads to non-traumatic amputation and finally even death. However, the mechanism of DFU is not fully understood. Interleukin 25 (IL-25), an alarmin cytokine that responds to tissue injury, has been reported to participate in tissue regeneration and maintaining glucose homeostasis. However, the role of IL-25 in diabetic wound healing remains unknown. Here, we showed that interleukin 17 receptor B (IL- 17RB), the functional receptor of IL-25, was significantly inhibited in the wound skin of both diabetic patients with DFU and streptozotocin (STZ)-induced diabetic mice. Topical administration of recombinant IL-25 protein improved angiogenesis and collagen deposition in the wound bed and thus ameliorated delayed diabetic wound healing. IL- 25 increased endothelial-specific CD31 expression in diabetic wounds and exogenous IL- 25 protected endothelial cells from high glucose-impaired cell migration and tube formation in vitro. We further revealed that IL-25-mediated-IL-17RB signaling rescued the downregulation of Wnt/b-catenin pathway both in vivo in diabetic mice and in vitro in HUVECs and induced the phosphorylation of AKT and ERK 1/2 in HUVECs under high glucose conditions. This study defines a positive regulatory role of IL-25-mediated-IL- 17RB signaling in diabetic wound healing and suggests that induction of IL-25-mediated  IL-17RB signaling may be a novel therapeutic strategy for treating poor healing diabetic wounds.

Keywords: IL-25, IL-17RB, diabetes mellitus, wound healing, endothelial cell functions.

Pin Deng,1 Hongshuo Shi ,2 Xuyue Pan ,1 Huan Liang ,1 Shulong Wang ,1Junde Wu,1 Wei Zhang ,3 Fasen Huang ,1 Xiaojie Sun ,1 Hanjie Zhu ,1and Zhaojun Chen1

1 Department of Hand and Foot Surgery, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing 100029, China

2 College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250000, China

3 Orthopaedic Center, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing 100029, China

Correspondence should be addressed to Zhaojun Chen; 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

Received 9 August 2021; Revised 18 December 2021; Accepted 5 January 2022; Published 27 January 2022

Academic Editor: Ferdinando Carlo Sasso

Copyright © 2022 Pin Deng et al. This is an open access article distributed under the Creative Commons Attribution License,

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

       Objectives. Diabetic foot ulcer (DFU) is one of the devastating complications of diabetes. It has high mortality and disability rates. The number of research articles on DFUs has increased. This study was designed to explore the global trends and research hotspots of DFUs to benefit researchers in shaping future research directions. Methods. Literatures relating to DFU from 2004 to 2020 were retrieved from the Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). The current status of DFU research (including publications, journals, the performances of relevant countries, institutions, and authors and the research trends and hotspots of DFU) was analyzed with the WoSCC. VOSviewer v1.6.10.0 was utilised for cocitation, coauthorship, cooccurrence analyses, and bibliographic coupling. Results. A total of 5869 publications on DFUs were retrieved. We performed a longitudinal review of publications over 17 years: 4500 articles and 865 review articles on DFUs published from 2004 to 2020 were analyzed. The total citation was 107,296. The USA (n = 1866), England (n = 606), and China (n = 599) were the three largest contributors. The University of Washington had the greatest number of publications within this time period (n = 103), and it had the most cooperative units and was in the core position in all research institutions, followed by the University of Manchester (n = 94) and the University of Miami (n = 92). Armstrong DG (91/1.69%) and Lavery LA (55/1.19%) should be regarded as scholars who have made outstanding contributions. The top journal with the greatest total link strength was Diabetes Care. Analysis showed that the global research hotspots of DFU focused on lower limb amputation, diabetic foot infection, and treatment and management of DFU. Studies on osteomyelitis, wound therapy and management, multidisciplinary integration and mechanism of DFUs, and its related diseases are the research fronts that should be closely watched in the future. Conclusions. This study revealed the current research status and hotspots in the domain of DFU over the past 17 years, which can help researchers to further pinpoint potential perspectives on hot topics and research frontiers.