J Drugs Dermatol. 2024 Sep 1;23(9):748-756. doi: 10.36849/JDD.8388.
Dermatoporosis (DP) is a condition associated with thinning skin layers and resultant fragility. Much of the thinning is related to fibroblast dysfunction, production of destructive inflammatory cytokines, breakdown of the extracellular matrix (ECM), and weakening of the dermo-epidermal junction. A major contributor to this change in the ECM milieu, previously under-considered, is cellular senescence, particularly involving the papillary dermal fibroblasts.
A series of experiments were undertaken to explore the impact of a combination of known actives on senescent cell status. Human keratinocytes and fibroblasts were cultured, and cytotoxicity tests were performed to determine the ideal concentration to avoid cell toxicity. Microdoses of Centella asiatica (0.005%) and mandelic acid (0.05%) were found to be ideal in avoiding any cytotoxicity. However, the challenge was then to assess the efficacy of these actives in this microdosed form. After exposing the cells to the compounds, RNA was isolated and sequenced. Moreover, a well-described ex vivo model using photodamaged skin was subjected to immunofluorescence to identify senescent cells (via p16INK4a), particularly in the papillary dermis, using the microdose formulation compared to untreated skin. In addition, JAG/NOTCH expression in the epidermal basal cells was evaluated to further understand the cellular senescence signaling mechanism.
Microdosing these two well-known agents had surprisingly significant synergistic effects in vitro, decreasing senescence-associated secretory phenotype (SASP) cytokines and the associated inflammation involved in the process. The ex vivo model revealed a significant (P<0.05) decrease in senescent cells in the papillary dermis and a significant increase (P<0.001) of JAG/NOTCH expression in the basal cells of the epidermis.
Using microdoses of two known agents, a novel approach produced an unexpected effect of reversal of dermal senescent cells and promoting an anti-inflammatory milieu. A gene expression analysis of the individual and combined actives validated these observations, followed by full formulation testing in an ex vivo model. The approach of limiting cellular senescence in dermal fibroblasts for managing DP is novel and provides an exciting new direction to address dermatoporosis. Clinical studies will follow. J Drugs Dermatol. 2024;23(9):748-756. doi:10.36849/JDD.8388.
皮肤骨质疏松症（DP）是一种与皮肤变薄和脆弱相关的病症。大部分变薄与成纤维细胞功能障碍、破坏性炎症细胞因子的产生、细胞外基质（ECM）的破坏以及表皮-真皮连接的减弱有关。以前被低估的 ECM 微环境变化的一个主要因素是细胞衰老，特别是涉及乳头真皮成纤维细胞。
进行了一系列实验来探索一系列已知活性物质对衰老细胞状态的影响。培养人角质形成细胞和成纤维细胞，并进行细胞毒性试验以确定避免细胞毒性的理想浓度。发现 0.005%的积雪草和 0.05%的杏仁酸微剂量最理想，可避免任何细胞毒性。然而，挑战在于评估这些活性物质在这种微剂量形式下的功效。在将细胞暴露于化合物后，分离并测序 RNA。此外，使用光损伤皮肤的成熟体外模型进行免疫荧光染色，以鉴定衰老细胞（通过 p16INK4a），特别是在与未处理皮肤相比的乳头状真皮中，使用微剂量制剂。此外，评估了表皮基底层中的 JAG/NOTCH 表达，以进一步了解细胞衰老信号转导机制。
这两种众所周知的药物的微剂量给药具有令人惊讶的显著协同作用，可减少衰老相关分泌表型（SASP）细胞因子和参与该过程的相关炎症。体外模型显示，在乳头状真皮中衰老细胞显著减少（P<0.05），表皮基底层中的 JAG/NOTCH 表达显著增加（P<0.001）。
使用两种已知药物的微剂量，一种新的方法产生了逆转皮肤衰老细胞和促进抗炎微环境的意外效果。对个体和联合活性物质的基因表达分析验证了这些观察结果，随后在体外模型中进行了全面的配方测试。限制真皮成纤维细胞中细胞衰老以治疗 DP 的方法是新颖的，为解决皮肤骨质疏松症提供了令人兴奋的新方向。将进行临床研究。J 皮肤病学杂志。2024;23(9):748-756. doi:10.36849/JDD.8388.
