Abstract
Diabetic ulcers bring about high morbidity and mortality in patients and cause a great economic burden to society as a whole. Since existing treatments cannot fulfil patient requirements, it is urgent to find effective therapies. In this study, the wound healing effect of topical notoginsenoside R1 (NR1) treatment on diabetic full-thickness wounds in type II diabetes mellitus (T2DM) was induced by the combination of a high-fat diet and streptozotocin (STZ) injection. NR1 significantly increased the wound closure rate, enhanced extracellular matrix (ECM) secretion, promoted collagen growth, increased platelet endothelial cell adhesion molecule-1 (CD31) expression, and decreased cleaved caspase-3 expression. RNA-Seq analysis identified ECM remodeling and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in NR1-mediated wound healing. Further experiments showed that NR1-treated wounds demonstrated higher expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and transforming growth factor-β1 (TGFβ1) and lower expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), interleukin-1β (IL-1β), and interleukin-6 (IL-6) than diabetic wounds. These investigations promote the understanding of the mechanism of NR1-mediated diabetic wound healing and provide a promising therapeutic drug to enhance diabetic wound healing.
Highlights
Diabetic ulcers are serious complications that may lead to amputation in diabetic patients [1, 2]
By applying RNA Sequencing (RNA-Seq) technology, we identified extracellular matrix related processes and inflammation as critical biological processes and Timp1 and Mmp3 as important targets in notoginsenoside R1 (NR1)-mediated wound healing
Our further experiment confirmed the inhibitory effect of NR1 on extracellular matrix (ECM) remodeling and inflammation, which was evidenced by low expression of matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 3 (MMP3), IL-1β, and IL-6 and higher expression of transforming growth factor-β1 (TGF-β1) and tissue inhibitor of metalloproteinase 1 (TIMP1)
Summary
Diabetic ulcers are serious complications that may lead to amputation in diabetic patients [1, 2]. Wound healing in diabetes is associated with a series of pathological processes [5], such as oxidative stress [6], persistent inflammation [7], and apoptosis [8], and a decrease in extracellular matrix (ECM) secretion, resulting in nonunion of diabetic wounds [9]. Macrophages and neutrophilic granulocytes aggregate slowly in the persistent inflammatory stage and correspond to increased inflammation in diabetic ulcer patients [10, 11], which is different from the inflammatory stage of normal wounds. At this time, the phagocytosis ability of leucocytes is impaired, and the existence time of inflammatory cytokines in wounds is prolonged, which inhibits the formation of granulation tissue and wound healing [12]. The ECM is expressed during wound healing and is essential for tissue repair, and its abnormality mainly affects the remodeling and proliferation stages of wound healing [9]
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