hirsutanone and Dermatitis--Atopic

The aim of the present study was to enhance a topical delivery of hirsutenone (HST), a naturally occuring immunomodulator, employing Tat peptide-admixed elastic liposomes (EL/T).. HST-loaded EL, consisting of phosphatidylcholine and Tween 80 (85:15 w/w%), were prepared using thin film hydration method. By adding Tat peptide to EL (0.16 w/w%), EL/T were formulated. The in vitro skin permeation of HST was examined using a Franz diffusion cell mounted with depilated mouse skin. Lesions for atopic dermatitis (AD) were induced by a topical application of diphenylcyclopropenone to NC/Nga mice. Therapeutic improvements of AD were evaluated by clinical skin severity scores. Immunological analyses on inducible nitric oxide synthase and cyclooxygenase-2 levels in the skin and interleukin (IL)-4, IL-13, immunoglobulin E, and eosinophil levels in the blood were also performed.. EL systems were superior to conventional cream, revealing greater flux values in a permeation study. The addition of Tat peptide further increased the skin permeation of HST. In an efficacy study with AD-induced NC/Nga mice, an HST-containing EL/T formulation brought a significant improvement in both skin severity score and immune-related responses for the levels of nitric oxide synthase, cyclooxygenase-2, IL-4, IL-13, immunoglobulin E, and eosinophils.. A novel EL/T formulation was successfully developed for topical delivery of HST to treat AD.

Topics: Animals; Catechols; Cyclooxygenase 2; Dermatitis, Atopic; Diarylheptanoids; Eosinophils; Gene Products, tat; Immunoglobulin E; Interleukin-13; Interleukin-4; Liposomes; Male; Mice; Nitric Oxide Synthase; Phosphatidylcholines; Polysorbates; Skin Absorption

Atopic dermatitis (AD) is a common inflammatory skin disease. The increasing prevalence and severity of AD have prompted the developments of safer, more effective drugs. Although topical corticosteroids have been used as first line therapy for AD, their potential side effects limit their clinical applications. To investigate the effect of hirsutenone (HIR), a diarylheptanoid compound, on AD-like skin lesions and other factors related to immune response is the aim of this paper Th2-related cytokines (IL-4, IL-5, IL-13), eosinophil, IgE inflammatory factors (COX-2, iNOS) levels were reduced in blood, lymphocytes, and tissue after HIR treatment. These results suggest that HIR might be an effective treatment for AD.

Topics: Administration, Cutaneous; Animals; Catechols; Cyclooxygenase 2; Dermatitis, Atopic; Diarylheptanoids; Disease Models, Animal; Eosinophils; Female; Immunoglobulin E; Injections, Intraperitoneal; Interleukins; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type II; Skin

The increasing prevalence and severity of atopic dermatitis during recent decades has prompted the development of safe and more highly effective drugs. Although topical corticosteroids have been used for more than 50 years as first line therapy for atopic dermatitis, their potential side effects limits their clinical uses. In light of this, steroid-free topical calcineurin inhibitors were developed and have been used in patients with moderate to severe atopic dermatitis. In the present study, we examined if hirsutenone suppressed the profiles of atopic dermatitis development in vitro via mimicry of calcineurin inhibitor actions in mouse splenocytes and RBL-2H3 mast cells. Our results showed that hirsutenone effectively inhibited T cell activation by blocking dephosphorylation of nuclear factor of activated T cells (NFAT). This inhibition was confirmed by inactivation of mitogen-activated protein kinases (MAPKs), which subsequently inhibited production of cytokine mRNAs (interleukin-2, -4, -5, -13 and interferon-gamma) after T cell receptor stimulation. We also showed that the early T cell activation marker, CD25, was suppressed in the presence of hirsutenone after T cell receptor stimulation with anti-CD3. Moreover, degranulation of mast cells was remarkably suppressed, comparable to that by cyclosporine A. This indicates that hirsutenone may specifically inhibit calcium-activated processes in both T cells and mast cells. Therefore, our results suggest that hirsutenone may be a new topical drug candidate, which probably acts by mimicking calcineurin inhibitor mechanisms.

Topics: Alnus; Animals; Antibodies; beta-N-Acetylhexosaminidases; Biomarkers; Biomimetics; Calcineurin Inhibitors; Catechols; CD3 Complex; Cell Proliferation; Cytokines; Dermatitis, Atopic; Diarylheptanoids; Extracellular Signal-Regulated MAP Kinases; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Lymphocyte Activation; Mast Cells; Mice; NFATC Transcription Factors; Plant Bark; RNA, Messenger; Signal Transduction; T-Lymphocytes; Th1 Cells; Th2 Cells

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Diarylheptanoids such as oregonin and hirstanonol are demonstrated to have anti-inflammatory and anti-oxidant effects. The present study was to investigate the effect of hirsutenone, one of the diarylheptanoids, against tumor necrosis factor (TNF)-alpha-stimulated responses in human keratinocytes. Hirsutenone attenuated the TNF-alpha-induced production of cytokine IL-8, prostaglandin E(2) and chemokine CCL27, and the formation of reactive oxygen/nitrogen species in keratinocytes. Immunosuppressants (dexamethasone and cyclosporin A) inhibited the TNF-alpha-elicited formation of IL-8, prostaglandin E(2) and CCL27, but did not affect formation of reactive species. Bay 11-7085 (an inhibitor of NF-kappaB activation) and anti-oxidant N-acetylcysteine attenuated the TNF-alpha-induced formation of inflammatory mediators and reactive species. Hirsutenone, dexamethasone, cyclosporin A and Bay 11-7085 inhibited the TNF-alpha-induced phosphorylation of inhibitory kappaB and the activation of nuclear factor (NF)-kappaB. The results show that hirsutenone seems to reduce the TNF-alpha-stimulated production of inflammatory mediators in keratinocytes by suppressing the activation of NF-kappaB that may be mediated by reactive oxygen species. The findings suggest that hirsutenone may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease.

Topics: Alnus; Catechols; Cell Survival; Cells, Cultured; Chemokine CCL27; Dermatitis, Atopic; Diarylheptanoids; Dinoprostone; Gene Expression Regulation; Humans; Interleukin-8; Keratinocytes; NF-kappa B; Phytotherapy; Plant Extracts; Tumor Necrosis Factor-alpha