Huang Shaobin, Deng Wuguo, Dong Yunxian, Hu Zhicheng, Zhang Yi, Wang Peng, Cao Xiaoling, Chen Miao, Cheng Pu, Xu Hailin, Zhu Wenkai, Tang Bing, Zhu Jiayuan
Department of Burn, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Department of Cosmetic and Plastic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Burns Trauma. 2023 Mar 1;11:tkad005. doi: 10.1093/burnst/tkad005. eCollection 2023.
Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs).
Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs.
Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways.
Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.
瘢痕疙瘩是难以治疗的异常纤维增生。褪黑素可用于抑制某些纤维化疾病的发展，但从未用于治疗瘢痕疙瘩。我们旨在探究褪黑素对瘢痕疙瘩成纤维细胞（KFs）的作用及机制。
采用流式细胞术、CCK-8 检测、蛋白质免疫印迹法、伤口愈合检测、Transwell 检测、胶原凝胶收缩检测和免疫荧光检测，以证明褪黑素对正常皮肤、增生性瘢痕和瘢痕疙瘩来源的成纤维细胞的作用及机制。研究了褪黑素与 5-氟尿嘧啶（5-FU）联合应用在 KFs 中的治疗潜力。
褪黑素显著促进 KFs 细胞凋亡，抑制其细胞增殖、迁移、侵袭、收缩能力及胶原蛋白生成。进一步的机制研究表明，褪黑素可通过膜受体 MT2 抑制 cAMP/PKA/Erk 和 Smad 信号通路，从而改变 KFs 的生物学特性。此外，褪黑素与 5-FU 联合应用显著促进 KFs 细胞凋亡，抑制其细胞迁移、侵袭、收缩能力及胶原蛋白生成。此外，5-FU 抑制 Akt、mTOR、Smad3 和 Erk 的磷酸化，而褪黑素与 5-FU 联合应用则显著抑制 Akt、Erk 和 Smad 信号通路的激活。
总体而言，褪黑素可能通过膜受体 MT2 抑制 Erk 和 Smad 信号通路，从而改变 KFs 的细胞功能，而与 5-FU 联合应用可通过同时抑制多条信号通路在 KFs 中发挥更强的抑制作用。
