Abstract
Chronic skin inflammatory diseases, such as atopic dermatitis, are associated with a dysfunctional skin barrier due to an increase in various inflammatory stimuli, for instance inflammatory cytokines and chemokines. In particular, CCL17 and CCL22 expression is increased in patients with chronic skin inflammation. In this study, we synthesized several α- and β-anomers of dihydroergosterol (DHE)-glycosides and assessed their effects on CCL17 and CCL22 expression. We confirmed that the β-anomers of DHE-glycosides were superior to α-anomers of DHE-glycosides in inhibiting CCL17 and CCL22 mRNA and protein expression. In addition, we determined that DHE-glycoside β-anomers showed strong inhibitory activity towards pro-inflammatory cytokine mRNA and protein expression, including that of TNF-α, IL-6, and IL-1β- in stimulated HaCaT cells. These results imply that DHE-glycoside α- and β-anomers should be separated during synthesis of drugs for chronic skin inflammation. Our results also suggest that β-anomers of DHE-glycosides may play an important role as new drugs for chronic skin inflammation because of their ability to inhibit the skin inflammatory biomarker proteins CCL17 and CCL22.
Highlights
Natural products from various plants with soap-like properties, such as saponins, have played an important role in medicine and daily life for thousands of years [1]
Our results indicate that β-anomers of DHE-glycosides inhibit the mRNA and protein expression of pro-inflammatory cytokines and chemokines in TNF-α/IFN-γ-activated HaCaT cells to a greater extent than the α-anomers of DHE-glycosides, and that this is likely because of the instability in solution of the α-anomers of DHE-glycosides
As shown in Scheme 1, β- and α-anomers (2–5) of DHE-glycosides can be prepared by acid-catalyzed Schmidt glycosylation of DHE with OH-protected sugars followed by deprotection
Summary
Natural products from various plants with soap-like properties, such as saponins, have played an important role in medicine and daily life for thousands of years [1]. Saponins are amphipathic glycosides grouped structurally by having one or more hydrophilic glycoside moieties combined with a lipophilic triterpene or steroid derivative, and have well characterized biological properties including hemolytic activity, molluscicidal activity, and anti-inflammatory activity [2]. We previously confirmed that spinasterol-glucose (1) (spinasterol-Glc, Figure 1), extracted and identified from natural herbs, exhibited potent anti-inflammatory activity and inhibited CCL17 mRNA and protein expression in TNF-α/INF-γ-stimulated HaCaT cells [3]. Spinasterol-Glc is difficult to obtain from either natural plant extracts or using synthetic methods. We previously designed and synthesized a new sterol, 5,6-dihydroergosterol (DHE or stellarsterol) that is structurally similar to spinasterol and more obtained. Of the Molecules 2019, 24, 371; doi:10.3390/molecules24020371 www.mdpi.com/journal/molecules
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