Differentially Expressed Wound Healing-Related Transcriptome in the Non-Healing Diabetic Ulcers
Differentially Expressed Wound Healing-Related Transcriptome in the Non-Healing Diabetic Ulcers
Zahra Azadian,1zahra dahaghin,2Razieh Dalirfardouei1,3,*
1. Faculty of New Sciences and Technologies in Medicine, Department of Medical Biotechnology, Hamadan University of Medical Sciences, Hamadan, Iran 2. Laboratory Sciences in Hamadan University of Medical Sciences, Hamadan, Iran 3. Faculty of New Sciences and Technologies in Medicine, Department of Medical Biotechnology, Hamadan University of Medical Sciences, Hamadan, Iran
Introduction: Cutaneous wound healing is a complex process and composed of sequential cascade events in which chronically unhealed wounds/ulcers cannot complete individual phases or the entire healing process. It should be noted that peripheral arterial disease (PAD) is the most common cause of non-healing ulcers, especially indiabetic patients. In fact, several factors can cause chronic wounds not to heal, but there is no doubt that diabetes plays a detrimental role in wound healing. Diabetic wounds are often characterized by excessive inflammation, decreased angiogenesis, wound hypoxia, and inadequate tissue perfusion. Dysregulated immune responses and impaired immune cell activation, proliferation, and survival also contribute to the pathogenesis of diabetic foot ulcers. The purpose of the research is to explore novel therapeutic target to overcome non-healing diabetic wounds.
Methods: miRNA data sets were achieved by searching in GEO database until September 2023. The studies containing high throughput miRNA dataset and work on both healthy and diabetic patients were selected for further analysis.
To identify differentially expressed genes (DEGs), eligible gene expression profiles were investigated using the GO2R package, |LogFc|>1, and adj.P.value<0.05. To create and analyze the protein-protein interaction networks, STRING (12.0) and Cytoscape software (Cytohubba and MCODE plugin) were applied. The miRSystem server was used. MiRNA target interactions were also determined using Mirwalk and miRTarBase. Finally, the DAVID database was used for finding significant molecular pathway, gene ontology, and enrichment analysis.
Results: According to the DEGs identified from 4 eligible datasets, miR-122 which has an effective role in inflammatory pathways such as mTOR, PI3K, and NF-kB as well as metabolic pathways, is a significant common miRs in both diabetics and diabetic + PAD patients. The key and hub genes in diabetic wounds compared with healthy wounds were CCL2, CXCL8, MMP9, and HBS1, which are involved in inflammatory processes, neutrophil chemotaxis, innate immune cell responses, angiogenesis, binding to collagen, integrin, and extracellular matrix supporting that these genes are promising candidates to prevent non-healing wound in the patients who suffers from diabetes. The target miRNAs for them via miRTarBase include hsa_miR_124_3p, hsa_miR_495_3p, and hsa_miR_183_5p.
Conclusion: Our findings confirmed that miR-122 contributes to the development of non-healing wounds especially in inflammatory process which is the first step of wound healing. Moreover, our study offers new potential targets to improve wound healing in patient with diabetic and diabetic + PAD.