Theophylline exerts complex anti-ageing and anti-cytotoxicity effects in human skin ex vivo
Theophylline exerts complex anti-ageing and anti-cytotoxicity effects in human skin ex vivo
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DOI：
10.1111/ics.12589
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发表时间：
2019-12-17
影响因子：
2.3
通讯作者：
Paus, R.
中科院分区：
文献类型：
--
作者：
Bertolini, M.;Ramot, Y.;Paus, R.
目的茶碱是一种磷酸二酯酶抑制剂，临床上用于治疗哮喘。此外，它被认为是一种可能具有抗衰老和抗氧化特性的化妆品。然而，它如何影响人类皮肤仍然没有得到很好的研究。方法离体人全层皮肤培养液中加入茶碱（10或100 μ M）24或72 h。结果茶碱刺激抗氧化剂金属硫蛋白-1的蛋白表达和I型和III型胶原的mRNA水平。免疫组织化学评估显示，真皮微纤维的结构稳定性增强。茶碱还通过降低MMP-2和MMP-9 mRNA水平发挥细胞外基质保护作用，部分拮抗甲萘醌（强效毒性ROS供体）的作用。此外，它减少甲萘醌刺激的表皮角质形成细胞凋亡。有趣的是，茶碱还增加了脑内产生的褪黑激素的水平，褪黑激素是最有效的ROS保护和DNA损伤修复神经介质，并倾向于增加褪黑激素受体MT 1的蛋白质表达。茶碱也增加了角蛋白15的表达，干细胞标记，在表皮基底层，但不改变线粒体活性或表皮色素沉着。结论茶碱具有多种复杂的皮肤保护作用。它鼓励进一步检查茶碱作为抗衰老治疗的局部候选药物。
Objective Theophylline is a phosphodiesterase inhibitor that is being used clinically for asthma therapy. In addition, it is recognized as a cosmetic agent with possible anti-ageing and anti-oxidative properties. Nevertheless, how it affects human skin is still poorly examined. Methods Theophylline (10 or 100 mu M) was administered to the culture medium of full-thickness human skin ex vivo for 24 or 72 h. Results Theophylline stimulated protein expression of the anti-oxidant metallothionein-1 and mRNA levels of collagen I and III. Assessment of fibrillin-1 immunohistology revealed enhanced structural stability of dermal microfibrils. Theophylline also exerted extracellular matrix-protective effects by decreasing MMP-2 and MMP-9 mRNA levels, partially antagonizing the effects of menadione, the potent, toxic ROS donor. In addition, it decreased menadione-stimulated epidermal keratinocytes apoptosis. Interestingly, theophylline also increased the level of intracutaneously produced melatonin, that is the most potent ROS-protective and DNA damage repair neuromediator, and tendentially increased protein expression of MT1, the melatonin receptor. Theophylline also increased the expression of keratin 15, the stem cell marker, in the epidermal basal layer but did not change mitochondrial activity or epidermal pigmentation. Conclusion This ex vivo pilot study in human skin shows that theophylline possesses several interesting complex skin-protective properties. It encourages further examination of theophylline as a topical candidate for anti-ageing treatment.