A novel mineralocorticoid receptor antagonist, 7,3',4'-trihydroxyisoflavone improves skin barrier function impaired by endogenous or exogenous glucocorticoids

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.

The myeloid mineralocorticoid receptor regulates dermal angiogenesis and inflammation in glucocorticoid‐induced impaired wound healing

“…A recent study extended the implication of GC-induced off-target MR activation in skin defects associated with psychological stress, acting through an increase in endogenous GC cortisol levels, which alters epidermal barrier function and worsens several common skin diseases, such as atopic dermatitis or psoriasis (Lee et al, 2021). This study showed that MR antagonism improved the deleterious consequences of GC on skin barrier function found in normal human epidermal keratinocytes and reconstructed human epidermis (Lee et al, 2021). Importantly, we observed in a previous study that Clobetasol pretreatment of mouse skin leads to an increased expression in the wound of epithelial sodium channels (ENaC), a target gene downstream of MR activation, that was blunted when the wound was treated with the MR blocker Canrenoate.…”

“…Biyashev et al recently reported that the association of vitamin D3 and the MR antagonist spironolactone improves the inflammation shift and therefore enhances wound healing induced by nitrogen mustard exposure (Biyashev et al, 2020 ). A recent study extended the implication of GC‐induced off‐target MR activation in skin defects associated with psychological stress, acting through an increase in endogenous GC cortisol levels, which alters epidermal barrier function and worsens several common skin diseases, such as atopic dermatitis or psoriasis (Lee et al, 2021 ). This study showed that MR antagonism improved the deleterious consequences of GC on skin barrier function found in normal human epidermal keratinocytes and reconstructed human epidermis (Lee et al, 2021 ).…”

“…At the present time, it is very difficult to know whether such heterodimers do exist in vivo, more specifically in the skin and in all cell types. Overall, we consider that reducing the MR occupancy by exogenous or endogenous GCs will be responsible for beneficial effects of MR blockade in several situations, such as glucocorticoids treatment, ageing, UV irradiation, diabetic delayed wound healing, and perhaps psychological stress (Hannen et al, 2017 ; Lee et al, 2021 ; Nguyen et al, 2016 ; Stojadinovic et al, 2016 ).…”

5α‐Tetrahydrocorticosterone: A topical anti‐inflammatory glucocorticoid with an improved therapeutic index in a murine model of dermatitis

“…GR tethering to AP‐1 also is implicated in negative feedback effects of glucocorticoids on CRH (Malkoski & Dorin, 1999), as well as through GR monomer binding to negative GREs, and this may provide a common mechanism to explain the lack of effects of 5αTHB on collagen integrity and the HPA axis. It is also possible that alternative receptors may be involved; for example, MR antagonists can alleviate glucocorticoid‐driven skin atrophy (Bigas et al, 2018; Lee et al, 2021; Maubec et al, 2015; Sevilla et al, 2020; Sevilla & Perez, 2018).…”