The elucidation of structure–activity and structure-permeation relationships for the cutaneous delivery of phytosterols to attenuate psoriasiform inflammation

Phytosterols have been reported to exert anti-inflammatory activity. This study aimed to investigate the capacity of campesterol, β-sitosterol, and stigmasterol on the mitigation of psoriasiform inflammation. We also tried to establish structure-activity and structure-permeation relationships for these plant sterols. To support this study, we first approached the in silico data of the physicochemical properties and the molecular docking of phytosterols with stratum corneum (SC) lipids. The anti-inflammatory activity of the phytosterols was explored in the activated keratinocytes and macrophages. Using the activated keratinocyte model, a significant inhibition of IL-6 and CXCL8 overexpression by phytosterols was detected. A comparable inhibition level was found for the three phytosterols tested. The macrophage-based study showed that the anti-IL-6 and anti-CXCL8 activities of campesterol were greater than those of the other compounds, which indicated that a phytosterol structure without a double bond on C22 and with methyl moiety on C24 was more effective. The conditioned medium of phytosterol-treated macrophages decreased STAT3 phosphorylation in the keratinocytes, suggesting the inhibition of keratinocyte hyperproliferation. β-sitosterol was the penetrant with the highest pig skin absorption (0.33 nmol/mg), followed by campesterol (0.21 nmol/mg) and stigmasterol (0.16 nmol/mg). The therapeutic index (TI) is a parameter measured by multiplying the cytokine/chemokine suppression percentage with skin absorption for anticipating the anti-inflammatory activity after topical delivery. β-sitosterol is a potential candidate for treating psoriatic inflammation due to having the greatest TI value. In this study, β-sitosterol attenuated epidermal hyperplasia and immune cell infiltration in the psoriasis-like mouse model. The psoriasiform epidermis thickness could be reduced from 92.4 to 63.8 μm by the topical use of β-sitosterol, with a downregulation of IL-6, TNF-α, and CXCL1. The skin tolerance study manifested that the reference drug betamethasone but not β-sitosterol could generate barrier dysfunction. β-sitosterol possessed anti-inflammatory activity and facile skin transport, showing the potential for development as an anti-psoriatic agent.