当前位置: X-MOL 学术Burns Trauma › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Inhibiting Hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction
Burns & Trauma ( IF 6.3 ) Pub Date : 2021-06-30 , DOI: 10.1093/burnst/tkab031
Jie Zhang 1 , Peilang Yang 1 , Dan Liu 1 , Min Gao 1 , Jizhuang Wang 1 , Tianyi Yu 1 , Xiong Zhang 1 , Yan Liu 1
Affiliation  

Background Diabetic foot ulcers characterized by delayed healing are one of the main complications of diabetes. Epidermal keratinocyte dysfunction has been found to play a pivotal role in the poor healing ability of diabetic wounds. In this study, we aimed to explore the relationship between c-Myc and its O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) modification and keratinocyte dysfunction in diabetic wounds. Methods Clinical wound samples were collected and a full-thickness skin defect wound model of diabetic rats was established. Re-epithelialization of wounds was observed by H&E staining and expressions of proliferating cell nuclear antigen, transglutaminase 1, loricrin, c-Myc and O-GlcNAc were measured by immunohistochemistry. The functional changes of proliferation, migration and differentiation of human immortalized epidermal cells (HaCaT) cells after overexpression or knockdown of c-Myc were observed. O-GlcNAcylation of c-Myc was confirmed using immunoprecipitation and proximity ligation assay. Stability of the c-Myc protein was measured using cycloheximide. Wound healing was observed after topical application of compounds that inhibited c-Myc or O-GlcNAc on diabetic wounds. Results Keratinocytes at the diabetic wound margin were characterized by active proliferation and division, slow migration and poor differentiation. Similar phenomena were observed in HaCaT cells cultured in 30 mM glucose and keratinocytes at the wound margin of the diabetic rats. The expression of c-Myc was increased in keratinocytes at the wound margin of diabetic rats, patients, and in HaCaT cells cultured with 30 mM glucose. Increased expression of c-Myc promoted the proliferation while inhibiting the migration and differentiation of the HaCaT cells, and inhibition of c-Myc promoted diabetic wound healing. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing. Conclusions Increased expression of c-Myc promoted abnormal proliferation and inhibited migration and differentiation of keratinocytes at the diabetic wound margin. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of c-Myc or O-GlcNAc alleviated delayed diabetic wound healing. These findings make c-Myc and O-GlcNAc potential therapeutic targets for diabetic wounds.

中文翻译:

抑制 c-Myc 的 Hyper-O-GlcNAcylation 通过减轻角质形成细胞功能障碍加速糖尿病伤口愈合

背景以延迟愈合为特征的糖尿病足溃疡是糖尿病的主要并发症之一。已发现表皮角质形成细胞功能障碍在糖尿病伤口愈合能力差中起关键作用。在本研究中,我们旨在探讨 c-Myc 及其 O-连接的 N-乙酰氨基葡萄糖 (O-GlcNAc) 糖基化 (O-GlcNAcylation) 修饰与糖尿病伤口中角质形成细胞功能障碍之间的关系。方法采集临床创面标本,建立糖尿病大鼠全层皮肤缺损创面模型。H&E染色观察创面再上皮化,免疫组化检测增殖细胞核抗原、转谷氨酰胺酶1、loricrin、c-Myc和O-GlcNAc的表达。增殖的功能变化,观察到 c-Myc 过表达或敲低后人类永生化表皮细胞 (HaCaT) 细胞的迁移和分化。使用免疫沉淀和邻近连接测定证实了 c-Myc 的 O-GlcNAcylation。使用放线菌酮测量c-Myc蛋白的稳定性。在糖尿病伤口上局部应用抑制 c-Myc 或 O-GlcNAc 的化合物后,观察到伤口愈合。结果糖尿病伤口边缘的角质形成细胞具有增殖分裂活跃、迁移缓慢、分化差的特点。在糖尿病大鼠伤口边缘的 30 mM 葡萄糖和角质形成细胞中培养的 HaCaT 细胞中也观察到了类似的现象。c-Myc 在糖尿病大鼠、患者伤口边缘的角质形成细胞和用 30 mM 葡萄糖培养的 HaCaT 细胞中的表达增加。c-Myc 表达增加促进增殖,同时抑制 HaCaT 细胞的迁移和分化,抑制 c-Myc 促进糖尿病伤口愈合。用 30 mM 葡萄糖增加 c-Myc 的 O-GlcNAcylation 稳定了 c-Myc 蛋白。抑制 O-GlcNAc 可改善角质形成细胞功能障碍并促进糖尿病伤口愈合。结论 c-Myc表达增加促进了糖尿病创面边缘角质形成细胞的异常增殖并抑制了迁移和分化。用 30 mM 葡萄糖增加 c-Myc 的 O-GlcNAcylation 稳定了 c-Myc 蛋白。抑制 c-Myc 或 O-GlcNAc 可缓解糖尿病伤口愈合延迟。这些发现使 c-Myc 和 O-GlcNAc 成为糖尿病伤口的潜在治疗靶点。
更新日期:2021-06-30
down
wechat
bug