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ABSTRACT: Steroids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways, that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time- and dose-dependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not sex steroids 17beta-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, that of mineralocorticoid receptor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when co-cultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus, steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of crosstalk between nuclear and cell-surface receptor signaling pathways.
AJP Cell Physiology 02/2013; · 3.54 Impact Factor
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ABSTRACT: The U box E3 ubiquitin ligase CHIP binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca(2+)/S100 proteins directly associate with the TPR-proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin-light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR-proteins with their target proteins. Therefore, we have hypothesized that Ca(2+)/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca(2+)/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca(2+)/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpressions of S100A2 and S100P suppressed CHIP-chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca(2+)-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.
Journal of Biological Chemistry 01/2013; · 4.77 Impact Factor
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ABSTRACT: Allergic and irritant skin diseases may be the results of representative inflammatory response in the skin. It has been established that inflammatory response includes reactive oxygen species, reactive nitrogen species, and free radicals. Subsequently, an imbalance between the oxidant and antioxidant components occurs; this is so-called oxidative stress. As various important roles of oxidative stress in contact dermatitis have been reported, controlling oxidative stress in these diseases could be a supplementary and/or novel therapeutic approach. However, there is little convincing clinical evidence that modulation of oxidative stress can be used therapeutically to modulate inflammatory response in allergic and irritant skin diseases. The reason for this discrepancy may be partially due to an insufficient understanding of the dynamics of oxidative stress in allergic and irritant skin diseases. This review introduces the importance of oxidative stress in allergic and irritant skin diseases from basic research to clinical management aspects. This review also introduces recent patents for the methods and compositions for the treatment of skin diseases with antioxidants. These methods may be helpful in treating allergic and irritant skin diseases through topical application of antioxidants.
Recent Patents on Inflammation & Allergy Drug Discovery 07/2012; 6(3):202-9.
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ABSTRACT: Disruption of skin barrier function leads to increases in the percutaneous transfer of allergens and the incidence of atopic dermatitis. Flaky tail (Flg(ft)) mice have been used as a model of atopic dermatitis with skin barrier dysfunction. Although Flg(ft) mice are known to have filaggrin mutation, the mechanism responsible for the skin barrier dysfunction that they display needs to be determined, especially for the roles of epidermal adhesion and junction proteins. Herein, we report the decreased expression of epidermal growth factor receptor (EGFR), E-cadherin, occludin, and SIRT1 in the skin of Flg(ft) mice, compared with those in C57BL/6J mice. Administration of N-acetyl-L-cysteine, an antioxidant, in the drinking water improved these protein expressions in the skin of Flg(ft) mice. Notably, we discovered that loricrin expression was suppressed in Flg(ft) mice. In vitro experiments showed that filaggrin small interfering RNA, loricrin small interfering RNA, or SIRT1 inhibitor sirtinol suppressed the expression levels of EGFR, E-cadherin, and occludin in a human immortalized keratinocyte cell line (HaCaT cells). Our findings suggest that the observed reductions in EGFR, E-cadherin, and occludin expression were due to filaggrin deficiency accompanied with subsequent loricrin deficiency and disruption of the SIRT1 pathway in the skin of Flg(ft) mice.
American Journal Of Pathology 07/2012; 181(3):969-77. · 4.89 Impact Factor
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ABSTRACT: Background: To improve health outcomes during the treatment for pruritic skin diseases, it is important to understand which factors most influence patients' concerns about oral antihistamine drugs. Objectives: To survey the nature of patients' concerns about oral antihistamine drugs and to examine the factors associated with them. Methods: Patients with pruritic skin diseases expressed their concerns regarding the use of oral antihistamine drugs. The independent effects of the patients' background characteristics on their concerns were examined by multiple logistic regression analysis. Results:A total of 291 outpatients were completed the study. Overall, 32% of patients were worried about using oral antihistamine drugs. The most common concern was about their adverse drug events (except drowsiness) and the effects of long-term use. Overall, being concerned about antihistamine use was found to be significantly and independently associated with a younger age, severe itching, being a homemaker, and having previous personal experience of embarrassment due to drowsiness caused by taking over-the-counter drugs. Conclusions:Several factors are associated with altered self-reported concerns about antihistamines. Our results suggest the importance of understanding the nature of patients' fears about oral antihistamine use so that sound advice can be offered to them in a timely manner.
Journal of Dermatological Treatment 05/2012; · 1.23 Impact Factor
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The Journal of Dermatology 04/2012; · 1.49 Impact Factor
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European journal of dermatology: EJD 03/2012; 22(3):427-8. · 2.53 Impact Factor
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European journal of dermatology: EJD 03/2012; 22(3):421-2. · 2.53 Impact Factor
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Annals of Dermatology 02/2012; 24(1):112-4. · 0.53 Impact Factor
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ABSTRACT: The relationship between the two coexpressed differentiation markers, profilaggrin and loricrin, is not clear right now. In this study, we explored the interaction of profilaggrin N-terminal domain (PND) with loricrin in keratinocytes and epidermis. Confocal immunofluorescence microscopic analysis of human epidermis showed that PND colocalized with loricrin. Loricrin nucleofected into HaCaT cells colocalized with PND in the nucleus and cytoplasm. The PND localizes to both the nucleus and cytoplasm of epidermal granular layer cells. Nucleofected PND also colocalized with keratin 10 (K10) in the nucleus and cytoplasm. Immunoelectron microscopic analysis of human epidermis confirmed the findings in nucleofected keratinocytes. Yeast two-hybrid assays showed that the B domain of human and mouse PND interacted with loricrin. The glutathione S-transferase (GST) pull-down analysis using recombinant GST-PND revealed that PND interacted with loricrin and K10. Knockdown of PND in an organotypic skin culture model caused loss of filaggrin expression and a reduction in both the size and number of keratohyalin granules, as well as markedly reduced expression of loricrin. Considering that expression of PND is closely linked to keratinocyte terminal differentiation, we conclude that PND interacts with loricrin and K10 in vivo and that these interactions are likely to be relevant for cornified envelope assembly and subsequent epidermal barrier formation.
Journal of Investigative Dermatology 01/2012; 132(4):1206-14. · 6.31 Impact Factor
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ABSTRACT: Juvenile xanthogranulomas are benign histiocytic cell tumors that develop mainly in infancy and early childhood and then spontaneously regress. We report a 2-year-old boy who presented with generalized eruption of a mixture of micronodular and macronodular juvenile xanthogranuloma with a large number of widely distributed lichenoid papules. Light microscopic and immunocytochemical analyses of the lesion were consistent with juvenile xanthogranuloma. Abdominal ultrasonography did not detect any visceral lesions, and brain magnetic resonance imaging did not detect any mass lesions. We decided to observe the course without treatment in this case because there are no internal masses of juvenile xanthogranuloma. Regular follow up has therefore been scheduled. To our knowledge, this is the third report of a case demonstrating juvenile xanthogranuloma with lichenoid appearance. Future analyses of various cytokines such as granulocyte-macrophage colony-stimulating factor and/or tumor necrosis factor-α in juvenile xanthogranuloma lesions should be of great help in elucidating the pathogenesis of this disease.
The Journal of Dermatology 10/2011; 39(5):462-5. · 1.49 Impact Factor
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The Journal of Dermatology 09/2011; 39(3):316-8. · 1.49 Impact Factor
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ABSTRACT: Cosmetic moisturisers were applied to one side of the face of 18 male Japanese patients with acne vulgaris who were treated with a topical administration of adapalene and clindamycin phosphate gels. We assessed the alleviating effect of the moisturisers on the side effects of the treatment. The severity of acne and the number of inflammatory and non-inflammatory lesions were measured at 0, 2, and 4 weeks. The water content in the stratum corneum and transepidermal water loss were measured by comparing the moisturiser-treated and untreated sides of the face. The sensation of skin dryness and irritation on both sides of the face were assessed by the subjects. We observed that the use of moisturisers did not impact the efficacy of the standard topical treatment and they significantly improved the water content in the stratum corneum and the sensation of dryness. These results suggested that the use of moisturisers in combination with the standard topical treatment may improve adherence to therapy by alleviating the sensation of dryness.
Journal of Dermatological Treatment 07/2011; 23(3):172-6. · 1.23 Impact Factor
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European journal of dermatology: EJD 06/2011; 21(4):616-7. · 2.53 Impact Factor
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European journal of dermatology: EJD 05/2011; 21(3):445-6. · 2.53 Impact Factor
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ABSTRACT: Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.
Experimental Dermatology 02/2011; 20(5):388-93. · 3.54 Impact Factor
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ABSTRACT: The efficacy of combined therapy with a retinoid and antibiotic for Japanese patients with acne vulgaris remains to be established. Further, maintenance strategies limiting the use of topical retinoids must be identified. The objectives of this study are to determine the efficacy of sequential application of topical adapalene and clindamycin phosphate and to assess the impact of this regimen on patients' quality of life. Sixty-six patients were recruited. The regimen comprised two phases. For the 4-week initial treatment, 1% clindamycin phosphate gel was applied twice daily and 0.1% adapalene gel, once. In the 4-week maintenance phase, patients were randomly assigned to the OD group (adapalene applied once daily) or the TW group (adapalene applied once daily on 2 days per week). The acne severity score, lesion counts, microcomedone count, and sebum amount were measured. Quality of life (QOL) was assessed using Skindex-16. All parameters improved significantly by week 4 of initial treatment. No statistically significant differences were found in the improvement of clinical findings between the groups. All QOL scores improved significantly and did not significantly differ between the groups. Our regimen may enable clinical control of acne in Japanese patients and improve their QOL. For limiting retinoid use, weekly application of adapalene during maintenance is suitable.
Journal of Dermatological Treatment 01/2011; 23(1):37-45. · 1.23 Impact Factor
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ABSTRACT: The epidermal cornified cell envelope is a complex protein-lipid composite that replaces the plasma membrane of corneocytes and is crucial for epidermal barrier function. Loricrin is a major constituent of the epidermal cornified cell envelope, contributing approximately 70% by mass. In order to explore novel function of wild-type (WT) loricrin other than the major component of the epidermal cornified cell envelope, we transiently expressed construct encoding human WT and mutant loricrin (730insG) in HaCaT keratinocytes. HaCaT cells transfected with WT or mutant loricrin were at differentiation level. WT loricrin in the transfected cells was seen diffusely in the cytoplasm and nuclei. Positive transferase deoxytidyl uridine end labeling staining was observed in the nuclei of WT loricrin-transfected HaCaT keratinocytes. Data from the DNA fragmentation assay showed that only WT loricrin induced DNA ladders compared with that of mutant loricrin. WT loricrin-transfected HaCaT keratinocytes were susceptible to programmed cell death (PCD). Activation of caspase-14 was also seen. In contrast, PCD or activation of caspase-14 did not occur in mutant loricrin-transfected HaCaT cells. These results suggest that the expression of WT loricrin facilitates induction of PCD in HaCaT keratinocytes.
The Journal of Dermatology 11/2010; 37(11):956-64. · 1.49 Impact Factor
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Ikuko Tsukamoto,
Norikazu Sakakibara,
Tokumi Maruyama,
Junsuke Igarashi,
Hiroaki Kosaka, Yasuo Kubota,
Masaaki Tokuda,
Hiromi Ashino,
Kenichi Hattori,
Shinji Tanaka,
Mitsuhiro Kawata,
Ryoji Konishi
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ABSTRACT: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100muM was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.
Biochemical and Biophysical Research Communications 09/2010; 399(4):699-704. · 2.48 Impact Factor
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ABSTRACT: In this community-based cross-sectional study, 1443 Japanese adolescents aged 13-19 years participated from two schools in Kagawa Prefecture. Students completed a self-administered questionnaire to assess the prevalence of acne, knowledge about acne, self-management of acne and emotional well-being. A five-item version of the Mental Health Inventory (MHI) subscale of the Short Form 36 was used to assess psychological health and depression status. Among respondents, 859 (59.5%) said they had acne (51.6% of the boys and 64.8% of the girls). A majority (56.8%) of those who said they had acne also reported a family history of acne. Of the 555 female respondents with acne, 39.1% reported experiencing acne flares in temporal proximity to menstruation. Less than half (38.8%) of respondents with acne had sought or were seeking treatment. The three most common factors believed to trigger or exacerbate acne were stress, lack of sleep and sweat. The mean MHI score of 847 students with acne was significantly lower than 475 students without acne. The mean MHI score of female students with acne was significantly lower than male students with acne. Students with acne were also significantly more depressed than those without acne and female students were significantly more depressed than male students. Acne is a common problem for Japanese teenagers and causes personal and social difficulties. Our results suggest the necessity of educational programs in school or public to ensure that adolescents are aware of acne and to encourage young people to improve their mental health through better acne treatment.
The Journal of Dermatology 07/2010; 37(7):617-22. · 1.49 Impact Factor
