School of Life Sciences and Biopharmaceutics, Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Eur J Pharmacol. 2022 Dec 5;936:175329. doi: 10.1016/j.ejphar.2022.175329. Epub 2022 Oct 29.
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-β, 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-β 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.
糖尿病创面愈合的特点是慢性炎症，仍然是一个医学挑战。从促炎 M1 样巨噬细胞向促愈合 M2 样巨噬细胞的迅速转化失败是糖尿病创面愈合的主要障碍。大黄素是一种蒽醌衍生物，具有多种生物活性，包括抗菌、抗癌和抗炎作用。最近，大黄素在促进伤口愈合方面显示出了潜力。然而，其潜在的分子机制尚不清楚。在这项研究中，我们使用全层切除模型研究了大黄素对 db/db 糖尿病小鼠伤口愈合的影响。结果表明，大黄素通过增强细胞外基质（ECM）合成和肉芽组织形成，显著加速愈合。我们通过网络药理学分析鉴定了 32 个大黄素的潜在靶点，我们的转录组分析强调了大黄素介导的 NF-κB 信号通路的下调。机制上，大黄素被证明可以抑制 p65-NF-κB 复合物，并在体外和体内促进 M2（抗炎）样表型巨噬细胞的比例。然后，将骨髓来源的巨噬细胞与成纤维细胞（小鼠真皮成纤维细胞）共培养。大黄素处理显著增加了共培养上清液中 M2 极化巨噬细胞的比例和 TGF-β的表达水平，TGF-β是 M2 巨噬细胞分泌的典型 ECM 形成相关细胞因子。我们进一步揭示，大黄素改善了小鼠真皮成纤维细胞（MDFs）细胞的增殖，并上调了大黄素处理共培养体系中 MDFs 细胞中胶原蛋白 III、纤维连接蛋白和α-SMA 的表达水平。1D11，一种针对所有三种主要 TGF-β 同工型的中和抗体，减弱了大黄素对 MDFs 细胞增殖和 ECM 形成的生物学作用。综上所述，我们的研究表明大黄素可能是治疗糖尿病创面的有效药物。
