Swindell William R, Bojanowski Krzysztof, Singh Parvesh, Randhawa Manpreet, Chaudhuri Ratan K
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
Sunny BioDiscovery, Inc., Santa Paula, California, USA.
JID Innov. 2022 Dec 26;3(3):100178. doi: 10.1016/j.xjidi.2022.100178. eCollection 2023 May.
The endocannabinoid (eCB) system plays an active role in epidermal homeostasis. Phytocannabinoids such as cannabidiol modulate this system but also act through eCB-independent mechanisms. This study evaluated the effects of cannabidiol, bakuchiol (BAK), and ethyl (linoleate/oleate) (ELN) in keratinocytes and reconstituted human epidermis. Molecular docking simulations showed that each compound binds the active site of the eCB carrier FABP5. However, BAK and ethyl linoleate bound this site with the highest affinity when combined 1:1 (w/w), and in vitro assays showed that BAK + ELN most effectively inhibited FABP5 and fatty acid amide hydrolase. In TNF-stimulated keratinocytes, BAK + ELN reversed TNF-induced expression shifts and uniquely downregulated type I IFN genes and (). BAK + ELN also repressed expression of genes linked to keratinocyte differentiation but upregulated those associated with proliferation. Finally, BAK + ELN inhibited cortisol secretion in reconstituted human epidermis skin (not observed with cannabidiol). These results support a model in which BAK and ELN synergistically interact to inhibit eCB degradation, favoring eCB mobilization and inhibition of downstream inflammatory mediators (e.g., TNF, COX-2, type I IFN). A topical combination of these ingredients may thus enhance cutaneous eCB tone or potentiate other modulators, suggesting novel ways to modulate the eCB system for innovative skincare product development.
内源性大麻素（eCB）系统在表皮稳态中发挥着积极作用。植物大麻素如大麻二酚可调节该系统，但也通过不依赖eCB的机制发挥作用。本研究评估了大麻二酚、补骨脂酚（BAK）和亚油酸乙酯/油酸乙酯（ELN）对角质形成细胞和重组人表皮的影响。分子对接模拟表明，每种化合物都与eCB载体FABP5的活性位点结合。然而，当BAK和亚油酸乙酯以1:1（w/w）组合时，它们与该位点的结合亲和力最高，体外试验表明BAK + ELN最有效地抑制了FABP5和脂肪酸酰胺水解酶。在TNF刺激的角质形成细胞中，BAK + ELN逆转了TNF诱导的表达变化，并独特地下调了I型干扰素基因和（）。BAK + ELN还抑制了与角质形成细胞分化相关的基因表达，但上调了与增殖相关的基因表达。最后，BAK + ELN抑制了重组人表皮皮肤中的皮质醇分泌（大麻二酚未观察到这种现象）。这些结果支持了一个模型，即BAK和ELN协同相互作用以抑制eCB降解，有利于eCB的动员和下游炎症介质（如TNF、COX-2、I型干扰素）的抑制。因此，这些成分的局部组合可能会增强皮肤eCB张力或增强其他调节剂的作用，为创新护肤品开发提供了调节eCB系统的新方法。
