Abstract
Excess glucocorticoids (GCs) with either endogenous or exogenous origins deteriorate skin barrier function. GCs bind to mineralocorticoid and GC receptors (MRs and GRs) in normal human epidermal keratinocytes (NHEKs). Inappropriate MR activation by GCs mediates various GC-induced cutaneous adverse events. We examined whether MR antagonists can ameliorate GC-mediated skin barrier dysfunction in NHEKs, reconstructed human epidermis (RHE), and subjects under psychological stress (PS). In a preliminary clinical investigation, topical MR antagonists improved skin barrier function in topical GC-treated subjects. In NHEKs, cortisol induced nuclear translocation of GR and MR, and GR and MR antagonists inhibited cortisol-induced reductions of keratinocyte differentiation. We identified 7,3’,4’-trihydroxyisoflavone (7,3’,4’-THIF) as a novel compound that inhibits MR transcriptional activity by screening 30 cosmetic compounds. 7,3’,4’-THIF ameliorated the cortisol effect which decreases keratinocyte differentiation in NHEKs and RHE. In a clinical study on PS subjects, 7,3',4'-THIF (0.1%)-containing cream improved skin barrier function, including skin surface pH, barrier recovery rate, and stratum corneum lipids. In conclusion, skin barrier dysfunction owing to excess GC is mediated by MR and GR; thus, it could be prevented by treatment with MR antagonists. Therefore, topical MR antagonists are a promising therapeutic option for skin barrier dysfunction after topical GC treatment or PS.
Highlights
Abbreviations PS Psychological stress 7,3’,4’-THIF 7,3’,4’-Trihydroxyisoflavone transepidermal water loss (TEWL) Transepidermal water loss stratum corneum (SC) Stratum corneum GC receptor (GR) Glucocorticoid receptor mineralocorticoid receptor (MR) Mineralocorticoid receptor GC Glucocorticoid fatty acids (FAs) Fatty acid
To determine whether cortisol activates both GR and MR, and whether the receptors are inhibited by their own antagonists, we examined the nuclear translocation of GR and MR in normal human epidermal keratinocytes (NHEKs) treated with mifepristone or eplerenone in the presence or absence of cortisol (Fig. 2 and S1)
Robust evidence supports that exogenous GC and endogenous GC under PS negatively affect the skin barrier function
Summary
Abbreviations PS Psychological stress 7,3’,4’-THIF 7,3’,4’-Trihydroxyisoflavone TEWL Transepidermal water loss SC Stratum corneum GR Glucocorticoid receptor MR Mineralocorticoid receptor GC Glucocorticoid FA Fatty acid. The mineralocorticoid receptor (MR) and GC receptor (GR) are members of the same nuclear receptor superfamily[16] Owing to their high structural similarity, the mineralocorticoid hormone, aldosterone, and cortisol, can bind to MR with high affinity[17,18]. Recent studies have highlighted that inappropriately activated MR caused by excess GC is involved in generating GC-mediated cutaneous side effects, such as delayed wound healing, epidermal atrophy, and skin aging. Such side effects can be prevented by topical MR blockade[25,26,27,28]. We hypothesized that MR inappropriately activated by GC mediates skin barrier dysfunction caused by exogenous GC or PS, and topical MR antagonism could prevent their detrimental effects on the skin barrier
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have