In atopic dermatitis, the concentration in the skin of sphingosylphosphorylcholine (SPC), which is produced from sphingomyelin by sphingomyelin deacylase, is increased. In the present study, we investigated the itch-eliciting activity of SPC and related substances and the mechanisms of SPC action in mice. An intradermal injection of SPC, but not sphingomyelin and sphingosine, induced scratching, an itch-associated response, which was not suppressed by a deficiency in mast cells or the H(1) histamine receptor antagonist terfenadine. The action of SPC was inhibited by the mu-opioid receptor antagonist naltrexone. SPC action also was inhibited by the 5-lipoxygenase inhibitor zileuton and the leukotriene B(4) antagonist ONO-4057, but not by the cyclooxygenase inhibitor indomethacin. Moreover, SPC action was inhibited by the antiallergic agent azelastine, which suppresses the action and production of leukotriene B(4). Administration of SPC to the skin and to primary cultures of keratinocytes increased leukotriene B(4) production. SPC increased intracellular Ca(2+) ion concentration in primary cultures of dorsal root ganglion neurons and keratinocytes. These results suggest that SPC induces itching through a direct action on primary afferents and leukotriene B(4) production of keratinocytes. Sphingomyelin deacylase and SPC receptors may be previously unreported targets for antipruritic drugs.

To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5-lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis.

Introduction: The periaqueductal gray mater (PAG) is considered to play an important

Among T1W MR imaging techniques, non-gated SE images can more accurately characterize intraplaque components in patients who underwent CEA when compared with cardiac-gated BB-FSE, MPRAGE, and SI-MRA images.

BackgroundHelicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.MethodsTo find candidate genes involved in stomach carcinogenesis, we firstly constructed a carcinogen-induced mouse gastric tumor model combined with H. pylori infection and high-salt diet. C57BL/6J mice were given N-methyl-N-nitrosourea in their drinking water and sacrificed after 40 weeks. Animals of a combination group were inoculated with H. pylori and fed a high-salt diet. Gene expression profiles in glandular stomach of the mice were investigated by oligonucleotide microarray. Second, we examined an availability of the candidate gene as prognostic factor for human patients. Immunohistochemical analysis of CD177, one of the up-regulated genes, was performed in human advanced gastric cancer specimens to evaluate the association with prognosis.ResultsThe multiplicity of gastric tumor in carcinogen-treated mice was significantly increased by combination of H. pylori infection and high-salt diet. In the microarray analysis, 35 and 31 more than two-fold up-regulated and down-regulated genes, respectively, were detected in the H. pylori-infection and high-salt diet combined group compared with the other groups. Quantitative RT-PCR confirmed significant over-expression of two candidate genes including Cd177 and Reg3g. On immunohistochemical analysis of CD177 in human advanced gastric cancer specimens, over-expression was evident in 33 (60.0%) of 55 cases, significantly correlating with a favorable prognosis (P = 0.0294). Multivariate analysis including clinicopathological factors as covariates revealed high expression of CD177 to be an independent prognostic factor for overall survival.ConclusionsThese results suggest that our mouse model combined with H. pylori infection and high-salt diet is useful for gene expression profiling in gastric carcinogenesis, providing evidence that CD177 is a novel prognostic factor for stomach cancer. This is the first report showing a prognostic correlation between CD177 expression and solid tumor behavior.