Sagami Womens Junior College

Sagamihara, Japan

Sagami Womens Junior College

Sagamihara, Japan
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Ishii M.,Showa University | Hagiwara T.,Sagami Womens Junior College | Mori Y.,Kyoto University | Shimizu S.,Showa University
Journal of Toxicological Sciences | Year: 2014

Ca2+ overload is one of the mechanisms for H2O2-induced cell death in rat pancreatic β-cell line RIN-5F cells. RIN-5F cells express TRPM2, which is a Ca2+-permeable channel activated by H2O2, and voltage-dependent L-type Ca2+ channels, both of which induce Ca2+ entry by H2O2. This study examined the contribution of these channels to H2O2-induced Ca2+ entry and cell death in RIN-5F cells. Cytosolic Ca2+ concentration was measured using fura-2 as a Ca2+ indicator. Cell death was estimated by trypan blue exclusion. Pre-treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, which inhibit TRPM2 activation, strongly reduced Ca2+ entry by H2O2. The PARP inhibitors used had no effect on the Ca2+ elevation by voltage-dependent L-type Ca2+ channels. On the other hand, pre-treatment with L-type Ca2+ channel blockers, which did not affect TRPM2 activation, partly reduced H2O2-induced Ca2+ entry. Treatment with PARP inhibitors but not L-type Ca2+ channel blockers, around the early phase in H2O2-induced Ca2+ elevation, also reduced the late phase. Moreover, H2O2-induced RIN-5F cell death was strongly attenuated by PARP inhibitors, in compared to L-type Ca2+ channel blockers. Our results suggest that TRPM2 channels rather than L-type Ca2+ channels primarily contribute to H2O2-induced Ca2+ entry and cell death.


Seike M.,Sagami Womens Junior College | Furuya K.,Sagami Womens Junior College | Omura M.,Sagami Womens Junior College | Hamada-Watanabe K.,Sagami Womens Junior College | And 2 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2010

Background: The present study observed effects of the histamine H 4 receptor on chronic allergic contact dermatitis induced by repeated challenge in mice. Methods: Acute contact dermatitis was induced by single epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene (TNCB) to the ear. Chronic allergic contact dermatitis was developed by repeated epicutaneous challenge using TNCB on the dorsal back skin. H4 receptor antagonist JNJ7777120 was administered to wild-type mice, while H4 receptor agonist 4-methylhistamine was administered to histidine decarboxylase (HDC) (-/-) mice that synthesized no histamine. Results: HDC (-/-) mice did not differ phenotypically from HDC (+/+) mice, and H4 receptor antagonist/agonist did not have clinical effects in terms of acute contact dermatitis reactions. H4 receptor antagonist ameliorated skin eczematous lesions induced by repeated TNCB challenge in HDC (+/+) mice. On the contrary, H4 receptor agonist exacerbated skin lesions exclusively in HDC (-/-) mice. Application of H4 receptor agonist induced migration of mast cells and eosinophils in skin lesions, and H4 receptor antagonist suppressed these changes. H4 receptor was immunohistochemically detected on mast cells in eczematous lesions. Levels of interleukin (IL)-4, -5, and -6 in lesions were decreased, whereas levels of interferon-γ and IL-12 were increased by H4 receptor antagonistic activity. Serum Immunoglobulin E levels rapidly increased with repeated challenge, but decreased with H4 receptor antagonist. Conclusion: Because chronic allergic contact dermatitis is developed by H 4 receptor stimulation, H4 receptor antagonists might represent new candidate drugs for treating chronic allergic contact dermatitis. © 2009 John Wiley & Sons A/S.


Shimizu S.,Yokohama College of Pharmacy | Shimizu S.,Showa University | Yonezawa R.,Showa University | Hagiwara T.,Sagami Womens Junior College | And 8 more authors.
European Journal of Pharmacology | Year: 2014

Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca2+-permeable channel that controls Ca2+signalling. The activation of Janus kinase 2 (Jak2) by oxidative stress is implicated in the production of inflammatory mediators. We found that AG490, a Jak2 inhibitor, had an inhibitory effect on H2O2-induced TRPM2 activation. The purpose of this study was to examine the underlying mechanisms of the inhibitory effects of AG490. Activation of TRPM2 in TRPM2-expressing human embryonic kidney 293 (TRPM2/HEK) cells or the human monocytic cell line U937 was monitored by fluorescence-based Ca2+imaging and patch-clamp techniques. Treatment with AG490 almost completely blocked H2O2-induced increase in intracellular Ca2+in TRPM2/HEK and U937 cells. In the patch-clamp study, AG490 inhibited the H2O2-evoked inward current but not the ADP-ribose-induced inward current in TRPM2/HEK cells. In contrast, Jak inhibitor 1 (pyridone 6) and staurosporine, both of which inhibit Jak2, had no effect on H2O2-induced increase in intracellular Ca2+. Moreover, AG490 decreased intracellular reactive oxygen species level, which was measured by using a hydroperoxide-sensitive fluorescent dye, on incubation with H2O2. In the cell-free assay system, AG490 scavenged hydroxyl radicals but not H2O2. These findings indicate that AG490 significantly reduces H2O2-induced TRPM2 activation, presumably by scavenging hydroxyl radicals rather than Jak2-dependent mechanisms. Although transient receptor potential ankyrin 1 (TRPA1) channel is also activated by H2O2, the H2O2-induced Ca2+entry through TRPA1 was only slightly delayed by AG490. This validates the potential use of AG490, as one of the materials for characterizing the role of TRPM2 channels in pathological models. © 2014 Elsevier B.V.


Tamaka K.,Sagami Womens Junior College | Seike M.,Sagami Womens Junior College | Hagiwara T.,Sagami Womens Junior College | Sato A.,Tohoku University | Ohtsu H.,Tohoku University
Experimental Dermatology | Year: 2015

Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-β1 in this model. Recombinant TGF-β1 or anti-TGF-β1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to determine the effects of histamine-regulated TGF-β on the Treg population in CACD. Recombinant TGF-β1 injection promoted the infiltration of Tregs in the skin and the production of IL-10; however, anti-TGF-β1 antibody injection suppressed the number of Tregs in the skin and the production of IL-10. Histamine suppresses the number of Tregs in CACD, and this effect is mediated by TGF-β. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Matsushita A.,Sagami Womens Junior College | Seike M.,Sagami Womens Junior College | Okawa H.,Sagami Womens Junior College | Kadawaki Y.,Sagami Womens Junior College | Ohtsu H.,Tohoku University
Experimental Dermatology | Year: 2012

Histamine facilitates development of eczematous lesions in chronic allergic contact dermatitis. In addition to the well-known corticosteroid treatments, H1 receptor (H1R) antagonists also have been used. This study observed effects of histamine H4 receptor (H4R) antagonist usage with H1R antagonist in a murine chronic allergic contact dermatitis model, developed by repeated percutaneous challenge to the dorsal skin with 2,4,6-trinitro-1-chlorobenzene (TNCB). The H1R antagonist olopatadine hydrochloride and/or the H4R antagonist JNJ7777120 was then administered. Combination therapy was more effective than H1R antagonist monotherapy. Serum IgE and levels of interleukin (IL)-4, IL-5 and IL-6 (Th2 cytokines) in eczematous lesions decreased with combined therapy. Combined therapy with H1R and H4R antagonists counteracts the disadvantages of each as monotherapeutic agents and potentially represents a new strategy for the treatment of chronic allergic contact dermatitis. © 2012 John Wiley & Sons A/S.


PubMed | Tohoku University and Sagami Womens Junior College
Type: | Journal: Handbook of experimental pharmacology | Year: 2016

In this chapter we will first introduce the pathophysiological process of several skin diseases including allergic dermatitis, a common skin disease, including chronic allergic contact dermatitis (CACD), and atopic dermatitis (AD). In CACD and AD patients, repeated skin exposure to antigens contributes to the development of chronic eczematous lesions. Repeated application of haptens on mice allows emulation of the development of CACD in humans. Further, we will focus on H1, H2, and H4 histamine receptors and their effects on CACD and AD. Histamine-deficient mice, with a knockout histidine decarboxylase (HDC) gene, were used to investigate the role of histamine in CACD and AD. Histamine induces infiltration of inflammatory cells, including mast cells and eosinophils, and elevates Th2 cytokine levels in CACD. Histamine promotes the development of eczematous lesions, elevates IgE serum levels, and induces scratching behavior in CACD. The administration of H1 or H4 receptor antagonists was effective to ameliorate these symptoms in murine CACD models. The combination of H1 and H4 receptor antagonists is a potential therapeutic target for chronic inflammatory skin diseases such as CACD and AD, since combined therapy proved to be more effective than monotherapy.


PubMed | Yokohama College of Pharmacy, Showa University, Kyoto University, Sagami Womens Junior College and Tohoku University
Type: | Journal: European journal of pharmacology | Year: 2014

Transient receptor potential melastatin 2 (TRPM2) is an oxidative stress-sensitive Ca(2+)-permeable channel that controls Ca(2+) signalling. The activation of Janus kinase 2 (Jak2) by oxidative stress is implicated in the production of inflammatory mediators. We found that AG490, a Jak2 inhibitor, had an inhibitory effect on H2O2-induced TRPM2 activation. The purpose of this study was to examine the underlying mechanisms of the inhibitory effects of AG490. Activation of TRPM2 in TRPM2-expressing human embryonic kidney 293 (TRPM2/HEK) cells or the human monocytic cell line U937 was monitored by fluorescence-based Ca(2+) imaging and patch-clamp techniques. Treatment with AG490 almost completely blocked H2O2-induced increase in intracellular Ca(2+) in TRPM2/HEK and U937 cells. In the patch-clamp study, AG490 inhibited the H2O2-evoked inward current but not the ADP-ribose-induced inward current in TRPM2/HEK cells. In contrast, Jak inhibitor 1 (pyridone 6) and staurosporine, both of which inhibit Jak2, had no effect on H2O2-induced increase in intracellular Ca(2+). Moreover, AG490 decreased intracellular reactive oxygen species level, which was measured by using a hydroperoxide-sensitive fluorescent dye, on incubation with H2O2. In the cell-free assay system, AG490 scavenged hydroxyl radicals but not H2O2. These findings indicate that AG490 significantly reduces H2O2-induced TRPM2 activation, presumably by scavenging hydroxyl radicals rather than Jak2-dependent mechanisms. Although transient receptor potential ankyrin 1 (TRPA1) channel is also activated by H2O2, the H2O2-induced Ca(2+) entry through TRPA1 was only slightly delayed by AG490. This validates the potential use of AG490, as one of the materials for characterizing the role of TRPM2 channels in pathological models.


PubMed | Sagami Womens Junior College
Type: Letter | Journal: Experimental dermatology | Year: 2012

Histamine facilitates development of eczematous lesions in chronic allergic contact dermatitis. In addition to the well-known corticosteroid treatments, H1 receptor (H1R) antagonists also have been used. This study observed effects of histamine H4 receptor (H4R) antagonist usage with H1R antagonist in a murine chronic allergic contact dermatitis model, developed by repeated percutaneous challenge to the dorsal skin with 2,4,6-trinitro-1-chlorobenzene (TNCB). The H1R antagonist olopatadine hydrochloride and/or the H4R antagonist JNJ7777120 was then administered. Combination therapy was more effective than H1R antagonist monotherapy. Serum IgE and levels of interleukin (IL)-4, IL-5 and IL-6 (Th2 cytokines) in eczematous lesions decreased with combined therapy. Combined therapy with H1R and H4R antagonists counteracts the disadvantages of each as monotherapeutic agents and potentially represents a new strategy for the treatment of chronic allergic contact dermatitis.


PubMed | Sagami Womens Junior College
Type: Journal Article | Journal: Clinical and experimental dermatology | Year: 2014

Repeated exposure to allergens induces chronic allergic lesions in the skin and a shift in the cutaneous cytokine milieu to T helper (Th)2.To assess the relationships between Th17 and Th2 response during allergic contact dermatitis (ACD) in mice.ACD was induced in C57BL/6 mice by single or repeated epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene. Relationships between Th17 and Th2 response were analyzed by immunohistochemical observations and activity of cytokines on days 8 (first challenge), 18 (11th challenge), 28 (21st challenge) and 38 (31st challenge).On day 8, tissue levels of interleukin (IL)-17 and IL-22 were high, whereas tissue levels of IL-4 and serum IgE concentration were low. Following acute contact dermatitis, mice developed chronic eczematous lesions on day 18, and gradually improved on days 28 and 38. Tissue IL-4 and serum IgE levels corresponded to the development and improvement of chronic eczematous lesions. Numbers of Th17 cells and tissue levels of IL-17 and IL-22 rapidly decreased as IL-4 and IgE levels increased on day 18. As levels of IL-4 and IgE decreased, the number of Th17 cells and tissue levels of IL-17 and IL-22 increased again on days 28 and 38. On day 18, tissue levels of Th17 response-inducing cytokines (IL-6, IL-23 and transforming growth factor-) were high, and IL-23-expressing cells appeared in abundance, when Th2 response was extremely high. IL-17 injection decreased tissue IL-4 and serum IgE levels.Th17 correlates closely with Th2 in murine chronic ACD induced by repeated epicutaneous challenge.


PubMed | Sagami Womens Junior College
Type: Journal Article | Journal: Experimental dermatology | Year: 2015

Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-1 in this model. Recombinant TGF-1 or anti-TGF-1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to determine the effects of histamine-regulated TGF- on the Treg population in CACD. Recombinant TGF-1 injection promoted the infiltration of Tregs in the skin and the production of IL-10; however, anti-TGF-1 antibody injection suppressed the number of Tregs in the skin and the production of IL-10. Histamine suppresses the number of Tregs in CACD, and this effect is mediated by TGF-.

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