Introduction: Aberrant Interleukin-33 (IL-33) activation is associated with numerous dermatological inflammatory and autoimmune diseases, such as atopic dermatitis, lupus, vitiligo and psoriasis. Thus, the inhibition of this pathway may provide therapeutic options in multiple pathologies. We hypothesized that targeting the IL-33 critical site of interactions with its membranal receptor, Suppression of Tumorigenicity 2 (ST2), will generate highly selective inhibitors capable of alleviating the detrimental effects of IL-33 activation. Methods: In silico-based methods for the identification of possible inhibitors of IL-33/ST2 interaction were used. Employing two structure-based pharmacophore models designed by LigandScout, a virtual screening of commercially available compounds and in house library revealed 13 compounds that may reduce level of IL-33/ST2 interaction. To verify their capacity to attenuate IL-33-induced inflammation, the compounds were tested in HMC-1.1 mast cell line and human skin slices. Results: Two lead compounds, both thiophene-benzimidazole conjugates methyl-1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate (LT-105) and methyl (S)-5-methyl-3-{(1-(pentan-3-yl)-2-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamido)}hexanoate (LT-108), were able to attenuate IL-33-induced IL-6 and IL 8 hypersecretion in pharmacological relevant concentrations. This effect correlated with reduced IL-6 and IL-8 mRNA levels, determined by RT-PCR. In addition, LT-105 and LT-108 reduced the phosphorylation of IL-33 downstream effectors; p-IRAK1 and p-P38. Further docking studies revealed possible molecular interactions of the compounds with key sites of IL-33 that are responsible for the binding with ST2. To validate the findings, the compounds were also tested in the ex vivo human skin organ culture. Both compounds LT-105 and LT-108 reduced inflammation when applied topically to the human skin samples stimulated by IL-33 in pharmacological concentrations. Conclusions: Our results indicate that thiophene-benzimidazole conjugates LT-105 and LT-108 can reduce IL-33 mediated inflammation both in vitro and ex vivo. Nevertheless, additional in vivo and clinical studies are required to further evaluate the ability of these compounds to treat autoimmune/inflammatory cutaneous disorders mediated by IL-33.
Purpose: Topical JAK inhibitors (JAKi) offer promising treatment for inflammatory skin disorders while minimizing systemic side effects. Understanding their pharmacokinetic and pharmacodynamic properties in skin is essential for their development. This pharmacokinetic study evaluated dermal penetration, metabolism, and stability of a novel, topical JAKi candidate and its inactive metabolite using dermal open flow microperfusion (dOFM) as a translational technology bridging ex vivo to in vivo findings. Patients and Methods: Skin penetration of parent compound (JAKi-o) was investigated ex vivo in human skin explants from three donors by dOFM sampling. Different test formulations (0.75%, 1.5%) and different dosing were compared with approved ruxolitinib 1.5% cream as reference. Stability and metabolic conversion into the inactive metabolite (JAKi-mb) were tested in extracted interstitial fluid and ex vivo after intradermal dOFM application. Results: Topical JAKi-o formulations (0.75%; 1.5%) produced dermal concentrations below the quantification limit (5 nM) at all timepoints. Reference ruxolitinib showed continuous concentration increases, reaching levels 63 times higher than the maximum JAKi-o concentrations. Pharmacokinetic profiles were consistent between explants and occlusion did not significantly affect dermal concentrations. Metabolic conversion in pure ISF was minimal, with only 14.4% of JAKi-o metabolized to JAKi-mb after 120 minutes. Intradermal application via dOFM confirmed intradermal metabolism, with a ratio of 1.6 (JAKi-o to JAKi-mb) during intradermal JAKi-o application which reversed to a ratio of 0.8 (JAKi-o to JAKi-mb) when only residual JAKi-o from the dermal tissue was available for metabolism. Conclusion: dOFM effectively detected dermal penetration and metabolism of small molecules in human skin ex-vivo, enabling prediction of human metabolization behaviour. This time-saving preclinical method supports early-phase drug development by determining whether compounds achieve sufficient skin concentrations without systemic availability, allowing early candidate selection and reducing development risks for topical therapies targeting epidermis and dermis.
OBJECTIVE: To evaluate the effects of a ceramide NP-containing soothing and moisturizing emollient cream on skin-barrier function in adult patients with atopic dermatitis (AD). METHODS: In this single-center, randomized, double-blind, placebo-controlled parallel trial, 60 adults with moderate atopic dermatitis were randomly assigned (1:1) to receive standard therapy with either the soothing and moisturizing emollient cream or placebo. Skin barrier parameters and clinical outcomes were assessed on Days 21 and 42. RESULTS: Both groups demonstrated overall improvements in skin barrier parameters, including stratum corneum hydration, TEWL, and casual sebum levels, with generally more favorable numerical trends observed in the intervention group. However, between-group differences in changes from baseline did not reach statistical significance, and no significant between-group differences were observed in skin surface pH. All clinical outcomes, including EASI, SCORAD, DLQI, and pruritus and insomnia VAS scores, improved significantly from baseline in both groups (P < 0.05), with numerically greater improvements generally observed in the intervention group and more pronounced improvements at Day 42 than at Day 21. CONCLUSION: This study evaluated the incremental value of the emollient under real-world clinical conditions. the soothing and moisturizing emollient cream showed favorable trends in improving skin barrier parameters and clinical symptoms in adults with AD when used as an adjunct to standard therapy. Larger, rigorously designed studies are warranted to confirm its efficacy and long-term clinical value.
Introduction: Photoaging and chronological age-related changes in cellular functioning such as telomere attrition can lead to accumulation of senescent skin cells, a key driver of age-related decline in skin integrity and function. Activation of sirtuins (SIRTs), master epigenetic regulators of cellular functioning and homeostasis in skin, may be a promising approach to protect skin cells from the effects of photoaging and cellular hallmarks of skin aging. Methods: In a series of in vitro studies, we evaluated the potential for a SIRT6 activator, a proprietary Hydrolyzed Yeast Protein Extract (HYPE), to modulate the response of normal human epidermal keratinocytes (NHEK) to UVB radiation, the rate of telomere attrition in dermal fibroblasts, and melanin content in melanocytes in a 3D skin model. Results: Treatment with HYPE increased SIRT6 protein expression in NHEK and SIRT6 gene expression in dermal fibroblasts, attenuated NF-κB-mediated inflammation in keratinocytes following UVB exposure, protected keratinocytes from DNA damage following UVB irradiation, decreased the rate of telomere attrition in aged dermal fibroblasts, and reduced melanin content in melanocytes in a 3D skin model. Conclusion: The potential for the SIRT6 activator HYPE to address multiple hallmarks of skin aging, and its activity in all 3 types of skin cells, makes it a potential agent to incorporate into skincare formulations designed to reverse visible aging.
Introduction: Lactic acid bacteria have various beneficial effects on humans and are widely used in the production of fermented foods. The whey generated by lactic acid bacteria during milk fermentation has been reported to increase the expression of skin moisturizing factors. This study aimed to elucidate the effects of whey on ultraviolet (UV)-induced skin pigmentation. Methods: The effects of α-melanocyte-stimulating hormone (α-MSH) alone or in combination with whey on melanin production were evaluated in mouse melanoma B16 cells. In addition, whey was topically applied to UV-irradiated HRM-2 mice, and the skin melanin content and the expression levels of melanogenesis-related enzymes (tyrosinase [TYR], tyrosinase-related protein 1 [TYRP1], and dopachrome tautomerase [DCT]) and microphthalmia-associated transcription factor (Mitf) were analyzed. Results: Whey significantly suppressed the α-MSH-induced melanin production increase in B16 cells in a concentration-dependent manner. UV irradiation significantly increased the skin melanin content in HRM-2 mice compared to that in the control group, which was markedly reduced by whey treatment. Furthermore, whey significantly inhibited the UV-induced upregulation of melanogenesis-related enzymes. Similarly, whey suppressed the expression of Mitf, a key transcription factor that regulates melanogenic enzyme expression. Conclusion: Topical application of whey suppressed UV-induced skin pigmentation by inhibiting Mitf expression, leading to reduced expression of downstream melanogenic enzymes, TYR, TYRP1, and DCT. These findings suggest that whey is a promising cosmetic ingredient for preventing or attenuating the progression of skin pigmentation.
