Elevated skin surface pH has been reported in patients with atopic dermatitis (AD). Here we explored the role of skin pH in the pathogenesis of AD using the NC/Tnd murine AD model. Alkalinization of the skin of asymptomatic NC/Tnd mice housed in specific pathogen-free (SPF) conditions induced KLK5 and activated the protease-activated receptor 2 (PAR2), resulting in thymic stromal lymphopoietin (TSLP) secretion and a cutaneous T-helper 2 allergic response. This was associated with increased trans-epidermal water loss and development of eczematous lesions in these SPF NC/Tnd mice, which normally do not suffer from AD. Injection of recombinant TSLP also induced scratching behavior in the SPF NC/Tnd mice. TSLP production and dermatitis induced by alkalinization of the skin could be blocked by the PAR2 antagonist ENMD-1068. In contrast, weak acidification of eczematous skin in conventionally housed NC/Tnd mice reduced kallikrein (KLK) 5　activity and ameliorated the dermatitis. Onset of the dermatitis was associated with increased epidermal filaggrin expression and impaired activity of the sodium/hydrogen exchanger NHE1, a known regulator of skin pH. We conclude that alterations in skin pH directly modulate KLK5 activity leading to skin barrier dysfunction, itch, and dermatitis via the PAR2-TSLP pathway.Journal of Investigative Dermatology accepted article preview online, 22 September 2015. doi:10.1038/jid.2015.363.

Since more than 75% of breast cancers overexpress estrogen receptors (ER), endocrine therapy targeting ER has significantly improved the survival rate. Nonetheless, breast cancer still afflicts women worldwide and the major problem behind it is resistance to endocrine therapy. We have previously shown the involvement of nuclear factor-κB (NF-κB) in neoplastic proliferation of human breast cancer cells; however, the association with the transformation of ER-positive cells remains unclear. In the current study, we focused on roles of NF-κB in the hormone dependency of breast cancers by means of ER-positive MCF-7 cells. Blocking of NF-κB signals in ER-negative cells stopped proliferation by downregulation of D-type cyclins. In contrast, the MCF-7 cells were resistant to NF-κB inhibition. Under estrogen-free conditions, the ER levels were reduced when compared with the original MCF-7 cells and the established cell subline exhibited tamoxifen resistance. Additionally, NF-κB participated in cell growth instead of the estrogen-ER axis in the subline and consequently, interfering with the NF-κB signals induced additive anticancer effects with tamoxifen. MMP-9 production responsible for cell migration, as well as the cell expansion in vivo, were suppressed by NF-κB inhibition. Therefore, we suggest that NF-κB is a master switch in both ER-positive and ER-negative breast cancers.

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Atopic dermatitis (AD) is a chronic inflammatory skin disease, with its major clinical feature being persistent itch sensation in the skin. There are extremely few animal models to reproduce the complicated condition of a patient with AD; therefore researchers have been confronted with some difficulties in pathologic analysis and drug development for AD. Although various models have been proposed and developed, there is no doubt that the spontaneous mouse model, NC mice, gave the greatest impact. NC mice enabled us to analyze pathogenesis of allergic skin abnormalities as well as development of new drugs for AD. However, many questions still remain in the pathogenesis of AD. In recent years, the study of the itch has attracted our attention because itch is one of the most unbearable symptoms of AD. For development of an effective treatment to overcome the itch, not only a precise animal model but also an accurate evaluation protocol are needed. This review summarizes some mouse models of AD, particularly focusing on NC mice, together with a novel evaluation system for scratching behavior of mice to help the understanding of researchers.

BackgroundBesides its anti-inflammatory effects, cinnamaldehyde has been reported to have anti-carcinogenic activity. Here, we investigated its impact on immune cells.MethodsActivation of nuclear factor-κB by cinnamaldehyde (0–10 µg/ml) alone or in combination with lipopolysaccharide was assessed in THP1XBlue human monocytic cell line and in human peripheral blood mononuclear cells (PBMCs). Proliferation and secretion of cytokines (IL10 and TNFα) was determined in primary immune cells and the human cell lines (THP1, Jurkat E6-1 and Raji cell lines) stimulated with cinnamaldehyde alone or in conjunction with lipopolysaccharide. Nitric oxide was determined in mouse RAW264.7 cells. Moreover, different treated PBMCs were stained for CD3, CD20 and AnnexinV.ResultsLow concentrations (up to 1 µg/ml) of cinnamaldehyde resulted in a slight increase in nuclar factor-kB activation, whereas higher concentrations led to a dose-dependent decrease of nuclear factor-kB activation (up to 50%) in lipopolysachharide-stimulated THP1 cells and PBMCs. Accordingly, nitric oxide, interleukin 10 secretion as well as cell proliferation were reduced in lipopolysachharide-stimulated RAW264.7 cells, PBMCs and THP1, Raji and Jurkat-E6 immune cells in the presence of cinnamaldehyde in a concentration-dependent manner. Flow cytometric analysis of PBMCs revealed that CD3+ were more affected than CD20+ cells to apopotosis by cinnamaldehyde.ConclusionWe attribute the anti-inflammatory properties of cinnamaldehyde to its ability to block nuclear factor-κB activation in immune cells. Treatment with cinnamaldehyde led to inhibition of cell viability, proliferation and induced apoptosis in a dose-dependent manner in primary and immortalized immune cells. Therefore, despite its described anti-carcinogenic property, treatment with cinnamaldehyde in cancer patients might be contraindicated due to its ability to inhibit immune cell activation.

Mineral ions in tap water react with fatty acids in soap, leading to the formation of insoluble precipitate (metallic soap) on skin during washing. We hypothesised that metallic soap might negatively alter skin conditions. Application of metallic soap onto the skin of NC/Tnd mice with allergic dermatitis further induced inflammation with elevation of plasma immunoglobulin E and proinflammatory cytokine expression. Pruritus and dryness were ameliorated when the back of mice was washed with soap in Ca2+- and Mg2+-free ultra-pure soft water (UPSW). Washing in UPSW, but not tap water, also protected the skin of healthy volunteers from the soap deposition. Furthermore, 4 weeks of showering with UPSW reduced dryness and pruritus of human subjects with dry skin. Washing with UPSW may be therapeutically beneficial in patients with skin troubles.

Mast cell tumours are one of the most common neoplasms in dogs. Mutations in the proto-oncogene c-kit, especially internal tandem duplications of exon 11, are considered to play a crucial role in mast cell tumourigenesis. In this report, two cases that suffered from multiple mast cell tumours containing an internal tandem duplication in the primary lesion but not in the secondary lesions are described. This finding indicates the existence of heterogenous c-kit gene mutations in each site of multiple mast cell tumours. Additionally, these results raise the possibility that the contribution of internal tandem duplications in the malignant transformation of mast cells is quite limited. It is proposed that, for clinicians, genetic analysis of several regions of multiple mast cell tumours is necessary for predicting prognosis and tumour response to KIT inhibitors.

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.