Abstract
Long-term hyperglycemia may lead to diabetic microvascular and macrovascular complications that can affect the peripheral vascular system, particularly in wound healing capacity. Impaired angiogenesis and delayed wound healing are significant clinically. Luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) is a naturally occurring flavonoid that is ubiquitously found in plants. Recent evidence has shown that luteolin is an anti-inflammatory and anti-oxidative agent. However, the effect of systemic luteolin administration on diabetic wound restoration remains unclear. Herein, we explored the effectiveness of luteolin for improving delayed and impaired healing of skin wound and further clarified the underlying mechanisms. The results indicated that luteolin significantly attenuates blood glucose concentration, improves impaired healing and accelerates re-epithelization of skin wound in streptozotocin (STZ)-induced diabetic rats. Histopathological staining and immunoblotting revealed an inhibitory effect of luteolin on inflammatory cell and cytokine production. We also observed remarkable decreases in protein expressions of inflammatory factors including matrix metalloproteinase (MMP)-9, tumor necrosis factor (TNF)-α, interleukin (IL-6), and IL1-β and downregulation of nuclear factor (NF)-κB, as well as increases in anti-oxidative enzymes such as superoxide dismutase 1 (SOD1) and glutathione peroxidase (GSH-Px) induced by nuclear factor erythroid 2-related factor (Nrf)-2 following luteolin supplementation. Furthermore, luteolin decreased the expression of vascular endothelial growth factor (VEGF) and increased the expression of ubiquitin carboxy-terminal hydrolase (UCH)-L1, as evidenced by angiogenesis and neuronal regeneration in completely healed wound. In conclusion, systemic administration of luteolin promotes wound restoration by ameliorating inflammation and oxidative stress through the inactivation of NF-κB and upregulation of Nrf2 in STZ-induced diabetic rats.
Highlights
We observed persistent hyperglycemia in the Diabetes mellitus (DM) group, while blood glucose level significantly decreased in the DML group, compared to the DM group, on day 5
Inflammation.ThereThereThe fore, we explored whether accelerated wound healing diabetic systemically adminfore, we explored whether accelerated wound healing in in diabetic ratsrats systemically adminisistered with luteolin may be due to modulation of the inflammatory response
To corroborate the acceleration of the healing process in diabetic rats systemically To corroborate the acceleration the healing process diabetic rats systemically administered with luteolin, we examined of angiogenesis capacity andinnerve regeneration with luteolin, angiogenesis capacity and nervehigher regeneration in inadministered skin wound biopsy samples. we Theexamined protein expression of vascular endothelial growth factor (VEGF)
Summary
Long-term hyperglycemia in patients with diabetes confers a higher risk for chronic complications due to accumulations of toxic substances in tissues, which are irreversible and lead to microvascular (retinopathy, nephropathy, and neuropathy) or macrovascular (coronary heart disease, peripheral vascular disease, and stroke) diseases [2,3,4]. Biomedicines 2021, 9, 761 associated with hyperglycemia has been traditionally linked to impaired wound healing. Wound healing is a multifaceted dynamic repair process of skin barrier breach that involves significant physiological events such as growth factors and cytokines in response to cellular immunity. In addition to immune response activation, impaired wound healing leads to overproduction of matrix metalloproteinases (MMPs), resulting in extracellular matrix degradation and failure to generate skin re-epithelialization [6,7,8]. Identifying a potential therapeutic candidate for preventing and delaying the onset of DM and its complications is of great interest
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