Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
Topadur Pharma AG, Grabenstrasse 11A, 8952 Schlieren, Switzerland.
Int J Mol Sci. 2022 Jun 20;23(12):6860. doi: 10.3390/ijms23126860.
Wound healing pathologies are an increasing problem in ageing societies. Chronic, non-healing wounds, which cause high morbidity and severely reduce the quality of life of affected individuals, are frequently observed in aged individuals and people suffering from diseases affected by the Western lifestyle, such as diabetes. Causal treatments that support proper wound healing are still scarce. Here, we performed expression proteomics to study the effects of the small molecule TOP-N53 on primary human skin fibroblasts and keratinocytes. TOP-N53 is a dual-acting nitric oxide donor and phosphodiesterase-5 inhibitor increasing cGMP levels to support proper wound healing. In contrast to keratinocytes, which did not exhibit global proteome alterations, TOP-N53 had profound effects on the proteome of skin fibroblasts. In fibroblasts, TOP-N53 activated the cytoprotective, lysosomal degradation pathway autophagy and induced the expression of the selective autophagy receptor p62/SQSTM1. Thus, activation of autophagy might in part be responsible for beneficial effects of TOP-N53.
创伤愈合病理学是老龄化社会日益严重的问题。慢性、不愈合的伤口在老年人和受西方生活方式影响的疾病患者（如糖尿病）中经常观察到，这些伤口会导致高发病率，并严重降低受影响个体的生活质量。支持适当伤口愈合的因果治疗仍然很少。在这里，我们进行了表达蛋白质组学研究，以研究小分子 TOP-N53 对原代人皮肤成纤维细胞和角质形成细胞的影响。TOP-N53 是一种双重作用的一氧化氮供体和磷酸二酯酶-5 抑制剂，可增加 cGMP 水平以支持适当的伤口愈合。与角质形成细胞没有表现出整体蛋白质组改变不同，TOP-N53 对成纤维细胞的蛋白质组有深远的影响。在成纤维细胞中，TOP-N53 激活了细胞保护、溶酶体降解途径自噬，并诱导选择性自噬受体 p62/SQSTM1 的表达。因此，自噬的激活可能部分解释了 TOP-N53 的有益作用。
