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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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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: 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
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ABSTRACT: Loricrin is a major constituent of the epidermal cornified cell envelope. Recently, heterozygous loricrin gene mutations have been identified in two dominantly inherited skin diseases, Vohwinkel syndrome with ichthyosis and progressive symmetric erythrokeratoderma, collectively termed loricrin keratoderma. We generated stable HaCaT cell lines that express wild-type (WT) loricrin and a mutant form found in Vohwinkel syndrome with ichthyosis, using an ecdysone-inducible promoter system. The cells expressing the mutant loricrin grew more rapidly than those expressing WT loricrin after induction for 5 days. Confocal immunofluorescence microscopy revealed that phospho-Akt occurred in the nucleolus where the mutant loricrin was also located. The level of activity of Akt kinase was about nine times higher in cells with the mutant than in those with WT loricrin. ERK1/2, the epidermal growth factor receptor, vascular endothelial growth factor (VEGF) receptor 2 and Stat3 were all phosphorylated in cells with the mutant loricrin. The docking proteins, Gab1 and c-Cbl, were also tyrosine-phosphorylated in these cells. Furthermore, chromatin immunoprecipitation assays showed that Stat3 protein bound to the VEGF promoter in cells with the mutant. Thus, this study suggests that VEGF release and the subsequent activation of VEGF receptor 2 link loricrin gene mutations to rapid cell proliferation in a cellular model of loricrin keratoderma.
Journal of Biological Chemistry 03/2010; 285(21):16184-94. · 4.77 Impact Factor
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European journal of dermatology: EJD 09/2009; 19(6):644-5. · 2.53 Impact Factor
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ABSTRACT: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of growth factors that have been implicated in skin patho-physiology. Although endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) appear to be involved in mitogenesis and chemotaxis in epidermal keratinocytes, the activation of eNOS and VEGF production induced by HB-EGF and its signaling mechanism remains undefined.
We examined possible signal transduction pathways by which HB-EGF leads to eNOS activation and VEGF production in human epidermal keratinocyte cell line (HaCaT cells).
The phosphorylation of epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK; p42/p44 MAPK), Akt and eNOS were examined by Western blotting analysis. VEGF production was determined by enzyme-linked immunosorbent assay. Various inhibitors were utilized to investigate the signaling mechanisms of eNOS activation and VEGF production.
HB-EGF-induced phosphorylation of EGFR with maximum phosphorylation at 1h. HB-EGF-induced phosphorylation of p42/p44 MAPK in a few minutes. It activated Akt with maximum phosphorylation at 1h and eNOS with maximum phosphorylation at 3h. The HB-EGF-induced eNOS activation was significantly blocked by the p42/p44 MAPK inhibitor U0126 and the phosphatidylinositol 3-kinase (P13K) inhibitor LY294002. HB-EGF increased VEGF production. The HB-EGF-induced VEGF production was blocked by U0126 and LY294002. Finally, the HB-EGF-induced activation of Akt and eNOS was suppressed by VEGF competitive antagonist, CBO-P11.
These results demonstrate that HB-EGF-induced eNOS activation depends on p42/p44 MAPK, PI3K/Akt pathways and endogenous VEGF in HaCaT cells.
Journal of dermatological science 07/2009; 55(3):170-8. · 3.71 Impact Factor
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European journal of dermatology: EJD 07/2009; 19(5):507-8. · 2.53 Impact Factor
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The Journal of Dermatology 07/2009; 36(6):353-4. · 1.49 Impact Factor
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Dermatologic Surgery 01/2009; 34(12):1729-32. · 1.80 Impact Factor
