A novel PPARß/FFA1 dual agonist Y8 promotes diabetic wound healing.

BACKGROUND: Diabetes ulcer is one of the leading causes of disability and death in diabetics. Y8 [(2-(2-fluoro-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy) phenoxy)acetic acid)], a dual agonist of peroxisome proliferation activated receptorß (PPARß) and free fatty acid receptor 1 (FFA1/FFAR1/GPR40), a new compound molecule with the potential for diabetes ulcer treatment. OBJECTIVE: To research the effect of the dual target agonist Y8 and its mechanism of action in the treatment of diabetic ulcers. METHODS: We have established a wound model in diabetic mice. After treatment with Y8, wound healing was evaluated by tissue pathology, reactive oxygen species (ROS) levels, and gene expression testing. Under high sugar conditions, the mechanism of Y8 affecting fibroblasts' proliferation and keratinocytes' migration is further studied. RESULTS: We found that Y8 accelerated wound healing and shortened healing time in diabetic mice. Granulation tissue generation and extracellular matrix (ECM) deposition were significantly increased in Y8-treated mice. Mechanistically, Y8 promotes keratinocyte proliferation by activating PPARß and migration of keratinocytes by triggering FFA1 in vitro. In addition, Y8 also decreased ROS levels in fibroblasts in vitro and in vivo by activating PPARß, reducing their release of superoxide anions. CONCLUSION: Our results suggest that PPARß/FFA1 dual agonist Y8 has the effect of promoting the healing of diabetic ulcer wounds in vivo and in vitro, and its therapeutic effect is better than that of single-target agonists.

Preparation and properties of boron affinity molecularly imprinted mesoporous polymers based on Mn-doped ZnS quantum dots.

Sialic acid (SA), known as N-acetyl neuraminic acid, is a natural 9-carbomonosaccharide derivative. SA has been widely applied in the early diagnosis of diseases as therapeutic target. However, the abundance of SA is very low in biological samples, which is usually interfered by the similar molecules coexisting at high abundance. Combining the advantages of high selectivity and specificity of molecularly imprinted technology, high specific surface area of mesoporous materials and excellent optical properties of quantum dots, we chose Mn-doped ZnS quantum dots as signal elements, and sialic acid as the template molecule. KH-4-MAPB with recognition ability to SA was synthesized by one-step hydrothermal method using thiolene click reaction as functional monomer. Based on the principle of boron affinity, molecularly imprinted polymers with highly ordered mesoporous structure were prepared, and the structure and fluorescence properties of fluorescent molecularly imprinted polymers were studied. FT-IR, XRD, TEM and nitrogen adsorption-desorption experiments were used to characterize the structure and morphology of the molecularly imprinted polymers. The results showed that the prepared molecularly imprinted polymers had highly ordered mesoporous structure and a large number of imprinted holes, which ensured the specific selectivity of the molecularly imprinted polymers. The fluorescence properties of MIMPs were characterized and analyzed by fluorescence spectra, equilibrium adsorption kinetics experiments were conducted and imprinting properties were recorded under different pH. The above experimental results showed that the fluorescence quenching was successfully achieved when the template molecule SA was captured by the molecularly imprinted polymer. When the concentration of SA was 1.25-100 × 10-2 g/L, the fluorescence quenching degree of MIMPs showed a fine linear relationship with SA. The correlation coefficient was 0.9946, and the detection equation was F0/F - 1 = 0.0215 [CSA] + 0.0241. MIMPs had a high recognition ability for SA, and the imprinting factor was 2.44. As a fluorescent sensor for SA, the response time of MIMPs was 20 min. When the buffer solution pH was 7, the imprinting factor was the largest. Under the best conditions, MIMPs revealed good selectivity and specificity for the fluorescence recognition of SA. MIMPS were also applied to the analysis of SA in real human serum samples with satisfactory results.

The Antimicrobial Peptide Esculentin-1a(1-21)NH2 Stimulates Wound Healing by Promoting Angiogenesis through the PI3K/AKT Pathway.

Delayed wound healing is a persistent medical problem mainly caused by decreased angiogenesis. Esculentin-1a(1-21)NH2 [Esc-1a(1-21)NH2], has broad-spectrum antibacterial properties which comes from frog skins. It has shown promise as a treatment for wound healing. However, its effects on angiogenesis as well as the mechanism by which esc-1a(1-21)NH2 enhanced wound healing remained unclear. In this study, we analyzed the structural properties and biocompatibility of esc-1a(1-21)NH2 and evaluated its effect on wound closure using a full-thickness excision model in mice. Our results showed that esc-1a(1-21)NH2 significantly accelerated wound healing by increasing collagen deposition and angiogenesis, characterized by elevated expression levels of platelet, endothelial cell adhesion molecule-1 (CD31) and proliferating cell nuclear antigen (PCNA). Furthermore, the angiogenic activity of esc-1a(1-21)NH2 was confirmed in vitro by various assays. Esc-1a(1-21)NH2 significantly promoted cell migration and cell proliferation in human umbilical vein vascular endothelial cells (HUVECs) via activation of the phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT) pathway, and upregulated the expression of CD31 at both mRNA and protein levels. The effect of esc-1a(1-21)NH2 on angiogenesis was diminished by LY294002, a PI3K pathway inhibitor. Taken together, this study demonstrates that esc-1a(1-21)NH2 accelerates wound closure in mice by promoting angiogenesis via the PI3K/AKT signaling pathway, suggesting its effective application in the treatment of wound healing.

Emodin accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization.

Diabetic wound healing, characterized by chronic inflammation, remains a medical challenge. The failure of prompt conversion from pro-inflammatory M1-like macrophage to pro-healing M2-like macrophage is the main obstacle to diabetic wounds. Emodin, an anthraquinone derivative, has multiple bioactivities, including antibacterial, anticancer, and anti-inflammatory. Recently, emodin has shown potential in promoting wound healing. However, the underlying molecular mechanism remains unclear. In this study, we examined the effects of emodin on wound healing in db/db diabetic mice using a full-thickness excision model. Our results showed that emodin can remarkably accelerate healing by enhancing extracellular matrix (ECM) synthesis and granulation tissue formation. We identified 32 potential targets of emodin by network pharmacology analysis, and our transcriptome analysis highlighted the down-regulation of the NF-κB signaling pathway mediated by emodin. Mechanistically, emodin was shown to inhibit the p65-NF-κB complex and promote the proportion of M2 (anti-inflammatory)-like phenotype macrophages both in vitro and vivo. Then, bone-marrow-derived macrophages were co-cultured with fibroblasts (mouse dermal fibroblasts cells). Treatment of emodin significantly increased the proportion of M2-polarized macrophages and the expression level of TGF-ß, a typical ECM formation-related cytokine secreted by the M2 macrophages in the co-cultured supernatant. We further revealed that emodin improved the proliferation of mouse dermal fibroblasts (MDFs) cells and upregulated the expression levels of collagen III, fibronectin and α-SMA in MDFs cells in emodin-treated co-culture systems. 1D11, a neutralizing antibody for all three major TGF-ß isoforms, diminished the biological effects of emodin on proliferation and ECM formation in MDFs cells. Taken together, our study suggests emodin may serve as an effective therapeutic agent for diabetic wounds.