Technical University of Munich, Munich, Germany.
College of Pharmacy, University of Florida, Gainesville, FL.
Aesthet Surg J. 2021 Mar 12;41(4):514-524. doi: 10.1093/asj/sjaa142.
Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts.
The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo.
We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis.
In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses.
The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.
缺氧诱导因子 1α（HIF-1α）是一种负责组织稳态和再生的转录因子，其功能在老年时会降低。除了缺氧外，铁的隔离也会刺激 HIF-1α。因此，我们分析了铁螯合剂地拉罗司（DFP）刺激真皮成纤维细胞的效果。
本研究的主要目的是量化体外刺激真皮成纤维细胞的 DFP 浓度，并将有效 DFP 浓度与 DFP 穿透表皮、到达真皮和体内激活 HIF-1α的能力相关联。
我们测量了经过 24 小时体外预处理后的年轻和成纤维细胞的细胞增殖、代谢活性、HIF-1α表达和乳酸脱氢酶水平。此外，我们用不同的细胞染色评估了细胞存活率和形态。最后，我们进行了一项透皮渗透研究，使用 1%的 DFP 局部制剂来量化达到真皮所需的浓度。
体外给予铁螯合治疗（156-312.5 µg/mL DFP）可激活多种抗衰老过程。在 24 小时内达到真皮的浓度为 1.5%（0.15 mg/mL），这与我们实验室分析的有效剂量非常吻合。
DFP 激活 HIF-1α可增强成纤维细胞的代谢、增殖和存活，同时降低乳酸脱氢酶水平。HIF-1α 的调节与关键再生酶和蛋白质的激活有关，从而具有抗衰老作用。因此，DFP 的抗衰老特性及其令人满意的皮肤渗透使其成为一种有前途的再生剂。
