Royal jelly (RJ) is secreted by honeybees and has been used as an apitherapy to obtain healthy skin since ancient times. However, the mechanism of the protective effects of RJ against skin aging and skin diseases caused by skin stress and its components have not been clarified. In this study, we attempted to understand the effect of RJ on epidermal function and observed that NAD(P)H quinone dehydrogenase 1 (NQO1) is significantly induced by RJ in keratinocytes. The expression of NQO1 was also increased in the 3D epidermal skin model. NQO1 is involved in antioxidation and detoxification metabolism, and we found that RJ protects against the epidermal stress caused by UVB and menadione through the upregulation of NQO1. We identified 10-hydroxy-2-decenoic acid (10H2DA), a major fatty acid in RJ, as an active compound in this reaction as it induced the expression of NQO1 and protected the skin against oxidative stress. We demonstrated that the protective effect of RJ against epidermal stress is mediated through the upregulation of NQO1 by 10H2DA.

Extracellular vesicles (EVs) secreted from adipose-derived stem cells (ADSCs) are known to exhibit collagen synthesis and migration activity in fibroblasts. These EVs can be used as a regenerative medicine and for cosmetic medicinal materials. Royal jelly (RJ) is produced from the hypopharyngeal and mandibular glands of honeybees (nurse bee), which contains apicin and 10-hydroxy-2-decenoic acid, compounds that promote fibroblast proliferation and collagen and elastin synthesis. Here, we investigated whether RJ could further enhance the physiological function of ADSC-EVs on fibroblasts. The findings confirmed that lyophilized RJ and enzyme-treated RJ enhanced the secretion of EVs by ADSCs, increasing the proliferation, migration, and collagen synthesis of fibroblasts compared to those induced by conventional ADSC-EVs. Bioinformatics analysis was conducted using various software programs, based on the data obtained from comprehensive gene expression and small RNA profiling analyses through next-generation sequencing; the results suggested that the RJ treatment of ADSC-EVs significantly enhanced the expression of genes related to extracellular matrix composition. Our findings suggest that the ADSC-EVs qualitatively altered using RJ could offer a more effective therapeutic material for regenerative and cosmetic medicine than conventional ADSCs-EVs.

Royal jelly (RJ), a natural product secreted by honeybees, is used in various topical products for skincare and aids in maintaining cutaneous homeostasis. However, the mechanism underlying the effect of RJ on the skin has not yet been fully explored. Our previous data indicated that the epidermal equivalents become thicker and contain more p63-expressing proliferative cells after the addition of RJ to the medium. Therefore, we examined the effect of RJ on the proliferative ability of human primary epidermal keratinocytes (HPEKs) in a two-dimensional culture here. We observed only a slight increase in the proliferation of cells with the addition of RJ, suggesting that it is not actively involved in the proliferation of HPEKs. However, population doubling was enhanced in the RJ-treated group in the long-term culture experiment, indicating that RJ inhibits senescence. Additionally, RJ suppressed cellular senescence by regulating the expression levels of ΔNp63, p16, and p21. These results were further confirmed by the presence of major fatty acids, such as 10-hydroxy-2-decenoic acid, in RJ. Overall, our data indicate that RJ can maintain epidermal stem cell properties by repressing senescence.