Bai Liangliang, Wu Linping, Zhang Changsheng, Liu Zhiwen, Ma Liang, Ni Jing, He Dezhen, Zhu Mingxuan, Peng Shaoyong, Liu Xiaoxia, Yu Huichuan, Lei Yuhe, Luo Yanxin, Zhang Yu, Wang Xiaolin, Wei Gang, Li Yingjie
School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.
Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Mater Today Bio. 2024 Apr 16;26:101056. doi: 10.1016/j.mtbio.2024.101056. eCollection 2024 Jun.
Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na transporters have been identified as a functional regulator of regeneration. However, the role of Na in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na ionophores that were employed to increase intracellular Na content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na ionophores replenish H to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.
糖尿病足溃疡（DFU）是糖尿病患者中一种高发病的并发症，因此需要开发创新药物来满足未被满足的医疗需求。钠离子（Na）是膜电位和渗透平衡的一种成熟的介质。最近，钠转运蛋白已被确定为再生的功能调节因子。然而，Na在哺乳动物伤口复杂愈合过程中的作用仍不清楚。在这里，我们发现低钠血症小鼠的皮肤伤口表现出难以愈合的表型。用于增加细胞内Na含量的钠离子载体可以促进角质形成细胞的增殖和迁移，并促进血管生成，表现出多种生物学活性。其中，莫能菌素A成为加速糖尿病皮肤伤口愈合动态的一种有前景的药物。从机制上讲，线粒体Na升高会减缓线粒体内膜流动性，促使活性氧（ROS）的产生，这被确定为莫能菌素A诱导伤口愈合改善的关键效应因子。同时，钠离子载体向线粒体基质补充H，导致线粒体能量代谢增强，以支持有效的伤口愈合程序。我们的研究揭示了Na的新作用，它是伤口愈合的关键决定因素。此外，它为开发钠离子载体作为治疗糖尿病患者慢性皮肤伤口的创新药物指明了路线图。
