Journal of Dermatological Science - Articles in Press

A group of atopic dermatitis without IgE elevation or barrier impairment shows a high Th1 frequency: Possible immunological state of the intrinsic type - Corrected Proof

2012-05-17

Summary: Background: Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier.Objective: To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition.Methods: Enrolled in this study were 21 AD patients with IgE<200kU/L (IgE-low group; 82.5±59.6kU/L) having unimpaired barrier, and 48 AD patients with IgE>500kU/L (IgE-high group; 8.050±10.400kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA.Results: The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus.Conclusion: The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response.

Impact of epidermal desquamation on tissue stores of iron - Corrected Proof

Leonard M. Milstone, Rong-Hua Hu, James D. Dziura, Jing Zhou — 2012-05-11

Abstract: Background: Although several billion corneocytes are shed from human skin daily, metabolic studies from 50 years ago led to the conclusion that corneocyte desquamation had no measurable impact on systemic protein or iron status in humans.Objective: To measure iron content of internal organs after introducing local genetic changes in epidermis that alter iron metabolism in skin.Methods: Iron was measured in tissues and blood from groups of animals 7 weeks after weaning in three different mouse models expressing a transgene in epidermis: a hyperproliferation model in which the HPV16 E7 gene causes a 3-fold increase in epidermal turnover; an epidermal iron sink model in which overexpression of the transferrin receptor causes a 3–4 fold increase of iron in epidermis; a systemic hemochromatosis knockout model that has been crossed with the epidermal iron sink model.Results: In the hemochromatosis model with the iron sink transgene in epidermis, there was a statistically significant reduction in non-heme iron in serum and in the liver and kidney. In all models there was a statistically significant reduction in non-heme iron in the kidney.Conclusion: Local changes in iron metabolism in epidermis can have a measurable impact on systemic iron metabolism. By implication, disruptions in epidermal homeostasis might affect systemic levels of trace nutrients, and circulating toxins might be remediated by sequestering them in epidermis.

Mechanism of Mitf inhibition and morphological differentiation effects of hirsein A on B16 melanoma cells revealed by DNA microarray - Corrected Proof

Myra O. Villareal, Junkyu Han, Kenjiro Ikuta, Hiroko Isoda — 2012-05-07

Abstract: Background: We have previously reported that hirsein A inhibits melanogenesis in B16 melanoma cells by downregulating the Mitf gene expression.Objective: In this study, microarray was employed to determine the transcriptional response of B16 cells to hirsein A (HA) treatment and to find out the mechanism underlying Mitf downregulation.Methods: DNA microarray, spotted with 265 genes for melanogenesis and signal transduction, was performed using the total RNA isolated from B16 cells treated with HA. Validation of the results was done using real-time PCR. In addition, real-time PCR using primers for Mda-7 gene and F-actin staining were performed. Transfection experiments were performed to knockdown the expression of the Mc1r gene to evaluate its role in the cell morphological change observed.Results: As expected, the expressions of the Mitf-regulated melanosome transport genes and the Mc1r gene were downregulated. Furthermore, the expressions of the MAPK pathway intermediates were either up- or downregulated. Genes associated with cell differentiation, such as Gadd45b, were upregulated and prompted us to determine the expression of the Il-24 (Mda-7) gene using real-time PCR. There was an increase in the Mda-7 mRNA expression in B16 and HMV-II melanoma cells, and in human melanocytes. To better visualize the cell morphology, F-actin staining was performed and the results showed an increase in the dendrite outgrowth in HA-treated cells. Silencing the Mc1r gene did not cause a change in the B16 cell morphology observed in cells treated with HA.Conclusion: This study demonstrated that HA downregulates Mitf gene expression by regulating the expressions of the MAPK signaling pathway intermediates. In addition, the inhibited Mc1r gene expression also contributed to the overall Mitf downregulation but does not play a role in the observed change in B16 cell morphology. HA surprisingly can regulate genes associated with differentiating cells (Mda-7) suggesting a role for HA in the melanoma cell differentiation induction. While the exact molecular mechanism by which HA promotes cell differentiation remain to be determined, it is clear that HA can downregulate Mitf expression and promote cell differentiation and has the potential to be used in the development of therapy for melanoma.

The antifungal effect of light emitting diode on Malassezia yeasts - Corrected Proof

Hyun Seung Wi, Eui Young Na, Sook Jung Yun, Jee-Bum Lee — 2012-05-01

Abstract: Background: Malassezia (M.) species are members of the normal part of the skin flora, but they might induce or be involved with various cutaneous diseases. Although the role of Malassezia in the pathogenesis of cutaneous diseases is not fully understood, recent studies have shown that decreased density of Malassezia led to improvement of these diseases.Objective: To identify the antifungal effect of light emitting diode (LED) against Malassezia, its antifungal mechanisms and the impact on the keratinocytes.Methods: LED with various wavelengths (370–630nm) on Malassezia furfur, Malassezia sympodialis and Malassezia globosa was irradiated according to dose and then the antifungal effects were thereafter assessed. After irradiating LED with 392.5±1nm of wavelength according to dose on Malassezia species, reactive oxygen species (ROS) and lipid hydroperoxide production assay were measured. In addition, cell viability and inflammatory cytokines (IL-1α, IL-1β, TNF-α, TGF-β, TLR-2 and COX-2) expressions in normal human epidermal keratinocytes (NHEKs) by LED irradiation were evaluated.Results: The growth of Malassezia species was dose-dependently suppressed by both LED with 380±2 and 392.5±1nm wavelengths. The increases of intracellular and extracellular ROS by LED irradiation with 392.5±1nm wavelengths were significantly observed compared to control group. The cell viability and cytokines in NHEKs were not significantly affected by LED irradiation under 5J/cm2 in vitro.Conclusion: LED irradiation with 380±2 and 392.5±1nm wavelengths proved to have antifungal effect against Malassezia species and no impact on NHEKs under 5J/cm2. The findings suggest that LED might be an adjunctive therapeutic light tool against Malassezia yeasts related cutaneous diseases.

Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis - Corrected Proof

Wen-Hung Chung, Shuen-Iu Hung — 2012-04-27

Abstract: Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65–75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas–FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.

Changes in photoinduced cutaneous erythema with topical application of a combination of vitamins C and E before and after UV exposure - Corrected Proof

2012-04-26

Abstract: Background: Ultraviolet radiation is harmful for human skin, and photodamaging pathologies such as actinic erythema, are formerly described as a consequence of UV direct effect on DNA and indirectly by local immune reactions. However, the degree of participation of oxidative stress in actinic erythema and the role of antioxidants in photoprotection are still not fully understood.Objective: To evaluate the possible palliative role of a combination of the antioxidants vitamins C and E in human cutaneous erythema when applied topically before and after UV exposure.Materials and methods: The study included 20 volunteers of phototypes II, II–III and III with no solar exposure for two months prior to the study. The volunteers were submitted to a phototest consisting on the analysis of the minimal erythemal dose (MED) under different treatments: 1. Untreated irradiated skin; 2. Irradiated skin previously treated with vehicle; 3. Irradiated skin previously treated with a combination of vitamins (2.5% vit E–5% vit C); and 4. Skin treated with the antioxidant combination after irradiation. Cutaneous erythema was evaluated 24h after exposure and the MED was calculated for each treatment.Results: The application of vehicle did not significantly affect the MED compared to untreated irradiated skin. Application of the antioxidant combination, prior to irradiation, increased the MED in all phototypes compared with untreated irradiated skin with an average increase of 36.9%. Antioxidants applied after exposure promoted an average increase of the MED by 19.8%.Conclusions: Combination of topical antioxidants (vitamins C and E) shows photoprotection activity against erythema, mainly owing to their high absorption properties. Moreover, their antioxidant activity could be considered as additive, and independent of their optical properties.

Assessment of BRAF and KIT mutations in Japanese melanoma patients - Corrected Proof

2012-04-25

BRAF- and KIT-activating mutations are established therapeutic targets in melanoma. In a recent trial, the BRAF inhibitor vemurafenib improved survival in patients with the BRAFV600E mutation . Similarly, the tyrosine kinase inhibitor imatinib is effective against melanomas with KIT mutations . Genetic mutations in BRAF and KIT are linked to specific melanoma subtypes. Cutaneous melanoma is classified into four subtypes: skin melanomas without chronic sun-induced damage (non-CSD), skin melanomas with chronic sun-induced damage (CSD), acral melanomas, and mucosal melanomas . Activating mutations in BRAF have been identified in at least 50% of non-CSD melanomas but are far less frequent in CSD, acral or mucosal melanomas . By contrast, KIT mutations are more common in acral and mucosal melanomas . These observations were made mainly in Caucasian populations. The mutation status of BRAF and KIT was recently assessed in the Chinese population , but has not yet been substantiated in other Asian populations. The present study examined BRAF and KIT mutations in Japanese melanoma patients because it is clinically important to determine the frequency of mutations likely to respond to BRAF- or KIT-directed therapies.

Long TSLP transcript expression and release of TSLP induced by TLR ligands and cytokines in human keratinocytes - Corrected Proof

Yang Xie, Toshiro Takai, Xue Chen, Ko Okumura, Hideoki Ogawa — 2012-04-20

Abstract: Background: Thymic stromal lymphopoietin (TSLP), highly expressed in keratinocytes in atopic dermatitis patients and bronchial epithelial cells in asthma patients, plays a key role in allergic diseases. Two forms of TSLP mRNA (long and short) have been reported.Objective: We compared the expression of the long-form and total TSLP transcripts in primary human keratinocytes.Methods: Primary human keratinocytes were stimulated with Toll-like receptor (TLR) ligands, cytokines, and vitamin D receptor agonists. Gene expression was analyzed by quantitative real-time PCR. The amount of TSLP released was measured by ELISA.Results: PolyI:C (TLR3 ligand), FSL-1 (TLR2–TLR6 ligand) and flagellin (TLR5 ligand) upregulated long-form TSLP expression, which predominantly contributed to upregulation of total TSLP expression. A glucocorticoid or an endosomal acidification inhibitor inhibited the polyI:C-dependent upregulation of total TSLP and the decrease of the total TSLP was due to the decrease of the long-form. An atopic cytokine milieu (TNF-α+IL-4+IL-13) or TNF-α alone also upregulated the long-form. These stimuli also induced the release of TSLP. In contrast, a high concentration of calcitriol (1,25-dihydroxyvitamin D3, the active form of vitamin D3) or its analog MC903 upregulated total TSLP significantly but not the long-form, and did not induce the release of TSLP.Conclusion: TLR ligands or cytokines predominantly upregulate the gene expression of the long TSLP form, which contributes to the TSLP protein production, in primary human keratinocytes. Specific measurement of the long-form rather than total TSLP should be useful for accurate detection of functional human TSLP gene expression.

NGF-p75 and neuropsin/KLK8 pathways stimulate each other to cause hyperkeratosis and acanthosis in inflamed skin - Corrected Proof

2012-04-20

It is well established that hyperkeratosis, acanthosis, and sprouting of peripheral nerve branches of sensory fibres occur in the epidermis of inflamed skin . Nerve growth factor (NGF) is thought to play an important role in this mechanism as its expression increases both in keratinocytes and cutaneous innervation in the epidermis of inflamed skin . Furthermore, we have established that NGF and its low affinity receptor, p75, induce hyperkeratosis, acanthosis, and sprouting of sensory fibres in the epidermis .

Over-expression of kallikrein related peptidases in palmoplantar pustulosis - Corrected Proof

2012-04-20

Pustulosis palmaris et plantaris or palmoplantar pustulosis (PPP) is a chronic pustular dermatitis characterized by palmoplantar intraepidermal vesicles filled with neutrophils. That very early vesicle formation occurs in the acrosyringium, and the sweat antimicrobial peptides, hCAP-18/LL-37 and dermcidin, are present in the vesicles of the palms and soles was discovered recently . Also, IL-17 positive cell infiltration around the acrosyringium as well as IL-17 expression in the acrosyringeal cells has been reported . However, despite progress in understanding the pathophysiology of vesicle and pustule formation in PPP, the mechanism(s) leading to the inflammatory, hyperkeratotic changes in the lesions remains unclear. Proteinase activity is necessary for the process of desquamation in human skin. Two major serine proteinases have been classified as members of the tissue kallikrein gene (KLK) family, and have been named, kallikrein related peptidases (KLK) 5 and 7, respectively. The presence of active enzyme , together with its ability to degrade desmosomal proteins at physiological pH suggests that KLK-5 and KLK-7 are involved in desquamation. In addition, KLK-14 also has been isolated and identified in its active form in the outermost layers of the stratum corneum . We examined the possibility of abnormal expression of KLKs in the early lesions of this disease process.

Relationship between microstructure of the skin surface and surface reflection based on geometric optics - Corrected Proof

Kenichiro Yoshida, Masahiro Miyaki, Nobutoshi Ojima, Kayoko Iwata — 2012-04-20

Abstract: Background: The behavior of reflected light in skin affects skin appearance and provides clues as to the internal condition of the skin. Surface topography is one of the central physical factors contributing to surface reflection.Objective: We tried to clarify the relationship between microstructure of the skin surface and surface reflection based on geometric optics.Methods: Microstructures and surface reflections in the left cheeks of adult females were evaluated. Skin topography was acquired measuring replicas using confocal laser microscopy. Surface topography was used to calculate arithmetical mean deviation of the surface (Sa), and geometric index from gradient of the surface (Sgrad), which is expected to correlate with the directionality of surface reflection (DoSR) based on geometric optics. A surface reflection image was acquired from differently polarized pictures of a face, and the index of surface reflection (Iobs) was calculated as the average pixel value of the area of shine. Correlations between indices were then evaluated.Results: Sgrad and Sa showed significant correlation (p<0.01) with Iobs. However, Sgrad showed a higher correlation with the simulated surface reflection from the reflection model than Sa. In addition, Sgrad can explain differences in DoSR for some panelists even in the case of an identical Sa.Conclusions: The topographic element involved in DoSR was extracted from height mapping. Sgrad reflects the ratio of flat area, offering a more effective indicator than Sa for distinguishing topographic characteristics with respect to surface reflection.

Pattern of tissue invasion by Propionibacterium acnes in acne vulgaris - Corrected Proof

2012-04-17

The human skin commensal bacterium, Propionibacterium acnes (P. acnes), is associated with inflammatory acne over all other members of the cutaneous microbiota ; however, there is still no formal proof of a causal link between P. acnes and acne. A major difficulty is the direct detection of P. acnes within acne-associated lesions. Microbiological evidence for P. acnes involvement in acne has mainly been derived from culture studies and therefore lacks precision with respect to sites of colonization within the skin micro-environments. Methodologies enabling direct visualization of bacteria, such as fluorescent in situ hybridization (FISH) and immunofluorecent microscopy (IFM) assays, either individually or combined are more accurate at establishing micro-environment colonization. We have designed an observational study where we sought to detect and co-localize P. acnes and inflammatory cells in acne lesions with the combined use of FISH, IFM, immunohistochemistry (IHC) and routine histochemistry assays.

Lack of integrin β5 in Merkel cell carcinomas and derived cell lines is frequently associated with Merkel cell polyomavirus positivity - Corrected Proof

2012-04-16

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin neoplasia. The Merkel cell polyomavirus (MCPyV), a double-stranded DNA tumour virus was discovered in 2008. It is found in approximately 80% of human MCC and is suspected to play a role in MCC development . Both, small tumour and the aminoterminal moiety of the large tumour antigen, were found to be expressed in MCPyV-positive MCC . Merkel cells are usually scattered in the basal cell layer of the epidermis along the dermo-epidermal junction .

UVA irradiation following treatment with topical 8-methoxypsoralen improves bleomycin-induced scleroderma in a mouse model, by reducing the collagen content and collagen gene expression levels in the skin - Corrected Proof

2012-04-09

Abstract: Background: Recent studies have demonstrated that systemic or topical PUVA therapy, i.e., ultraviolet A (UVA) irradiation following treatment with 8-methoxypsoralen (8-MOP), is effective against the sclerotic skin lesions in systemic sclerosis. However, the mechanisms still remain unknown.Objective: To clarify the mechanisms of this therapy, we created a mouse model of bleomycin (BLM) injection-induced scleroderma and evaluated the effects of PUVA on the fibrotic lesions of scleroderma in this mouse model.Methods: BLM was injected subcutaneously once a day into the mice for 24 days. During the injection period, one group of mice was irradiated with UVA following local application of 8-MOP. Control groups were also set up, which were injected with phosphate-buffered saline, instead of BLM. Skin tissue samples examined histopathologically changes, measured of the content of hydroxyproline, and checked for the expression of genes encoding type I collagen, type III collagen, and transforming growth factor-β1 (TGF-β1).Results: The mouse models of scleroderma was found to show an increase in the density of the collagen fibers and thickening of the dermis and increased expressions of type I collagen, type III collagen, and TGF-β1. However, the combination of BLM treatment and topical PUVA treatment mice appeared reduced the dermal thickness and hydroxyproline content, down-regulation of expressions of the type I and type III collagen genes was observed while the expression of the TGF-β1 gene remained unchanged.Conclusion: These results suggest that the effectiveness of topical PUVA therapy is attributable to the down-regulation of the expressions of the collagen genes by this treatment. The results additionally suggest that is not mediated by down-regulated expression of the TGF-β1.

Photodynamic therapy using a novel photosensitizer, TONS501, is similarly effective to ALA and EC036 photodynamic therapy on DMBA-and TPA-induced mouse skin papilloma - Corrected Proof

2012-04-05

Abstract: Background: Although topical photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) is applied for skin tumors including actinic keratosis, Bowen disease, and squamous cell carcinoma, there are no approved photosensitizers in dermatological field in Japan. TONS501 and TONS504 are novel hydrophobic photosensitizers with anionic and cationic chemical characteristics, respectively.Objective: Using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-ο-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin papilloma model, we compared the efficacy of ALA-, TONS501-, and TONS504-PDT on the skin tumor regression.Methods: Following application of ALA, TONS501, TONS504 ointment or TONS501 lotion on DMBA- and TPA-induced mouse papillomas, 670nm laser irradiation by LD670-05 diode laser was performed. Then tumor regression rate was calculated at the indicated time.Results: The anti-tumor effect of ALA, TONS501, and TONS504 ointment was detected at 24h and the maximal response was observed at 3day following the PDT treatment. The maximal response was observed at 150J/cm2 irradiation in all 3 photosensitizers. Although both ALA, TONS501 (ointment)-PDT showed more potent anti-tumor effect compared with that of TONS504 ointment or TONS501 lotion, no significant difference was detected between ALA ointment and TONS501 ointment.Conclusion: A novel TONS501ointment-PDT shows potent anti-tumor effect on DMBA- and TPA-induced mouse skin papilloma and might be more useful for the clinical applications.

Biological contribution of UVA wavelengths in non extreme daily UV exposure - Corrected Proof

2012-04-05

Chronic sun exposure leads to long term clinical skin alterations such as photoaging and photocarcinogenesis, involving both ultraviolet B (UVB) (280–320nm) and UVA (320–400nm) wavelengths. To study the impact of solar UV exposure occurring in most outdoor activities, a non-zenithal UV spectrum has been defined as standard ultraviolet daylight spectrum with a UVA to UVB irradiance ratio of around 27, corresponding to 96.5% UVA and 3.5% UVB. This non zenithal exposure can be reproduced in laboratory experimentations using a daily UV radiation (DUVR) spectrum , including a high and constant proportion of UVA wavelengths. Clinical and biophysical alterations as well as dermal and epidermal changes have been reported in human following exposure to repeated sub-erythemal doses of DUVR . The present study aimed at better characterizing the biological contribution of UVA in DUVR spectrum, using human reconstructed skin. This three dimensional model is composed of a dermal equivalent with living fibroblasts and a fully differentiated epidermis. It has been shown to be a useful tool for in vitro assessment of solar UV effects .

HOXA5 inhibits keratinocytes growth and epidermal formation in organotypic cultures in vitro and in vivo - Corrected Proof

2012-04-05

Abstract: Background: Homeobox transcription factors play important roles in epidermal renewal. Among them HOXA5 emerges as a promising member. However, its direct effect on epidermal biology, either to promote or to inhibit growth, is still controversial.Objective: We proposed to unravel the role of HOXA5 in modulating keratinocytes growth and epidermal formation in organotypic cultures both in vitro and in vivo.Methods: We transfected HaCaT cells with lentivirual vectors which over-expressed either wild-type or mutant HOXA5 cDNAs with deleted homeodomain. Subsequently we propagated the cells in organotypic cultures (OTCs) and then transplanted them into nude mice. Cell proliferation and cell cycle progression were detected. Epidermal morphogenesis and stratification were investigated by immunohistochemistry and immunofluorescence staining of a series of epidermal markers.Results: HaCaT cells transfected with HOXA5 cDNAs displayed lower growth rate and delayed G1-S transition. HOXA5-transfected OTC exhibited an aberrantly organized epithelium with significantly increased TUNEL staining as well as decreased PCNA and K5 staining, while expression of differentiation markers as K10, involucrin and filaggrin were somewhat enhanced. However, under in vivo environment in nude mice which had great paracrine regulatory mechanisms, the aberrant phenotype was ameliorated as shown by a more regular tissue organization and normal expression of PCNA and K5. Inversely, cells transfected with the homeodomain-deleted protein exhibited accelerated growth and produced a more proliferative and better-orchestrated epidermis, as shown by well-expressed proliferation and differentiation markers.Conclusions: HOXA5 can suppress keratinocytes growth and epidermal formation. It probably activated antagonist genes against growth factors release, which depends on its homeodomain.

Kojic acid-induced IL-6 production in human keratinocytes plays a role in its anti-melanogenic activity in skin - Corrected Proof

2012-04-05

Abstract: Background: Kojic acid is a fungal metabolite widely used in medicinal and cosmetic formulations as a skin-lightening agent based on its de-pigmenting activity. Although in human clinical studies kojic acid has been shown to be effective in the treatment of hyper-pigmentation disorders such as melasma, the reasons for its apparent lack of anti-melanogenic activity in cultured mammalian melanocytes are unclear.Objectives: This study was aimed to elucidate pharmacological mechanisms of the in vivo anti-melanogenic activity of kojic acid in human skin.Methods: A primary human melanocyte and keratinocyte co-culture system was used to evaluate whether kojic-acid-induced changes in keratinocytes were associated with anti-melanogenic activities in melanocytes. The cytokine secretion profiles in response to kojic acid were analyzed.Results: Kojic acid increased interleukin (IL)-6 and IL-8 production in melanocyte/keratinocyte co-cultures; however, IL-6 directly inhibited melanogenesis whereas IL-8 did not. In melanocyte monocultures, kojic acid did not increase IL-6 production whereas in keratinocyte monocultures it significantly up-regulated IL-6 gene and protein expression. Therefore, the up-regulation of IL-6 in melanocyte/keratinocyte co-cultures seems to be originated from kojic acid-induced changes in keratinocytes. Anti-IL-6 antibody treatment antagonized the anti-melanogenic effect of kojic acid on the co-cultures.Conclusions: The pharmacological mechanism of kojic acid to explain clinically effective anti-melanogenic activity on hyper-pigmented skin is associated with the kojic acid-induced IL-6 production in keratinocytes. The cross-talk between melanocytes and keratinocytes should be determined in future studies on the pharmacological mechanisms of clinically effective dermatological drugs acting on the epidermis.

Poly(A) tail shortening correlates with mRNA repression in tropoelastin regulation - Corrected Proof

2012-04-04

Abstract: Background: It has been shown for various organisms that expression of tropoelastin (TE) is high during fetal and neonatal growth and that it is reduced in adulthood by an unknown mechanism.Objective: To highlight the process of TE mRNA repression in vivo, total RNA from human skin biopsies was analyzed and TE mRNA expression was compared in fetal and adult donors.Methods: TaqMan Real-Time PCR, Poly(A) tail length assay, immunoblot.Results: In this study a more than 30-fold reduction of mature TE mRNA was detected whereas the decline on pre-mRNA level was not pronounced. This finding supports the hypothesis that the repression of mature TE mRNA is for the most part due to posttranscriptional mechanisms. Since deadenylation-dependent mRNA destabilization is the major decay pathway for most mRNAs, poly(A) tail length of mature TE mRNA was analyzed in fetal and adult human skin, lung and uterus, showing a profound reduction of poly(A) tail length in the adult samples. While TE mRNA is repressed in adult tissues in vivo, TGF-ß1 has been shown to induce expression of TE mRNA in vitro on the posttranscriptional level. To analyze the underlying mechanism, TE mRNA poly(A) tail length was analyzed in human dermal fibroblasts after treatment with TGF-ß1 in vitro. Besides the expected increase in TE expression, TGF-ß1 treatment resulted in a significant stabilization of TE mRNA poly(A) tail length.Conclusion: Our findings correlate for the first time TE expression level with poly(A) tail length and suggest that maintenance of poly(A) tail and deadenylation of TE mRNA might be general mechanisms involved in the regulation of TE expression.

Histological localization of aluminum in topical aluminum chloride treatment for palmar hyperhidrosis - Corrected Proof

2012-03-19

Primary or secondary hyperhidrosis is excessive sweating beyond that required for returning body temperature to normal. It can be focal or generalized and commonly affects the underarms, palms, soles or face . The disease often significantly affects the patient's quality of life. Treatment options include topical aluminum chloride (AC), iontophoresis, botulinum toxin A, oral anticholinergics, and endoscopic sympathectomy. Topical AC is a well-established therapy for hyperhidrosis and is the first-line therapy for mild to moderate disease . The mechanism of the action of aluminum (Al) salt in the forearm or axilla has been investigated in a few studies . However, there has been no report on the mechanism of the antiperspirant action of AC for treatment of palmoplantar hyperhidrosis. In this study, we investigated the histological localization of Al for palmar hyperhidorosis by using an Al specific binding fluorescence reagent and we investigated the mechanism of the antiperspirant action of AC.

Decreased repair of singlet oxygen-induced DNA damage in xeroderma pigmentosum group A cells determined by plasmid host cell reactivation - Corrected Proof

2012-02-29

To the Editor Xeroderma pigmentosum (XP) is a photosensitive genodermatosis that includes seven groups (A through G) with defective nucleotide excision repair (NER) and a variant form with defective translesional repair of ultraviolet (UV)-induced DNA damage. Patients with XP have severe sunsensitivity and a high frequency of skin cancers on sun-exposed areas. In addition, 30% of XP patients show progressive neurological degeneration . In Japan, half of XP patients belong to XP group A (XP-A), the most severe form of neurological symptoms, however, the molecular mechanism underlying the neurological abnormalities remains unproven .

Eleven novel mutations of the ADAR1 gene in dyschromatosis symmetrica hereditaria - Corrected Proof

2012-02-16

Dyschromatosis symmetrica hereditaria (DSH: MIM#127400) shows an autosomal dominant pattern of inheritance with high penetrance, which is characterized by hyperpigmented and hypopigmented macules on the face and dorsal aspects of the extremities. The phenotypes commonly appear in infancy or early childhood . In Asia, the condition occurs predominantly among Japanese and Chinese individuals. Previous study have clarified that a heterozygous mutation of the adenosine deaminase acting on RNA1 (ADAR1, formerly DSRAD) gene causes DSH in Japanese DSH families . The human ADAR1 spans 30kb and contains 15 exons. It encodes RNA-specific adenosine deaminase composed of 1,226 amino acid residues. The enzyme has two Z-alpha domains, three dsRNA binding domains and the deaminase domain . To date, more than 90 mutations have been reported from East Asian countries so far , which confirmed that the ADAR1 gene is responsible for DSH not only in Japanese but also in other ethnic groups. ADAR1 protein catalyzes the deamination of adenosine to inosine in double-stranded RNA substrates , which results in the creation of alternative splicing sites or alternations of the codon and thus leads to functional changes in the target protein. The ADAR1 gene is expressed ubiquitously, but the target RNA(s) in the skin as well as the mechanisms by which mutations in ADAR1 gene cause DSH still remain unknown. DSH patients are heterozygous for the ADAR1 gene mutation that is inherited as a dominant trait. Unlike patients with DSH, mice that are heterozygous for Adar1 gene deletion did not manifest any skin symptom. Homozygous Adar1 gene deletion was embryonic lethal. Recently epidermis-specific Adar1 gene knockout mouse model was generated . Histologically these mice showed massive necrosis of epidermis in FAB background mice, and thickened keratinocyte and stratum corneum in B6 background mice. Therefore, Adar1 was thought to be an essential molecule for skin integrity. In this study, we describe mutation analyses of Japanese families with DSH. The mutational analysis of the ADAR1 gene was performed as previously described . Informed consent and blood samples of patients were obtained under protocols approved by the Ethics Committee of Yamagata University School of Medicine.

Rare hereditary autoinflammatory disorders: Towards an understanding of critical in vivo inflammatory pathways - Corrected Proof

Nobuo Kanazawa — 2012-02-15

Abstract: Hereditary autoinflammatory syndromes are monogenic disorders with an inborn error of innate immunity, and include periodic fever syndromes such as familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS), pyogenic diseases such as pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPAS), and granulomatous diseases such as Blau syndrome. By identifying the genetic abnormalities and subsequent analyses of the molecular mechanisms underlying these disorders, several critical in vivo pathways for inflammatory processes have been discovered. In this review, three categories of autoinflammatory disorders are discussed: inflammasomopathies, receptor antagonist deficiencies and proteasome disability syndromes. Inflammasomopathies are diseases with dysregulated NLRP3 inflammasome activation, and include CAPS with NLRP3, FMF with MEFV, and PAPAS with PSTPIP1 mutations. Analyses of these diseases have clarified some critical pathways regulating NLRP3 inflammasome signaling. Receptor antagonist deficiencies include the newly defined deficiency for interleukin-1 receptor antagonist resulting in sterile multifocal osteomyelitis with periostosis and pustulosis, and deficiency for interleukin-36 receptor antagonist resulting in generalized pustular psoriasis. The identification of these genetic abnormalities has revealed a critical role for receptor antagonists of IL-1 family cytokines in regulating neutrophil activation/recruitment. Finally, proteasome disability syndromes with PSMB8 mutations include Nakajo-Nishimura syndrome and related disorders distributed globally. Analyses of these diseases have unexpectedly shown a critical role of the ubiquitin–proteasome system in the regulation or homeostasis of inflammation/metabolism. Since there still remain a number of predicted but undefined hereditary autoinflammatory syndromes, further clinical and genetic approaches are required to discover novel in vivo critical inflammatory pathways.

The suppressive effects of ultraviolet radiation on immunity in the skin and internal organs: Implications for autoimmunity - Corrected Proof

Gary M. Halliday, Diona L. Damian, Sabita Rana, Scott N. Byrne — 2012-01-25

Abstract: Low doses of sunlight that can be received during normal daily activities suppress immunity in humans. Both ultraviolet (UV) B (290–320nm) and UVA (320–400nm) are immunosuppressive. The wavelength dependence in humans shows distinct non-overlapping immunosuppressive peaks of solar effectiveness centred at 310nm UVB and 370nm UVA. In murine models of systemic immunosuppression low dose UV inhibits expansion of effector T cells in skin-draining lymph nodes, and retention of dermal effector memory CD8T cells at sites of antigen challenge. In addition to suppressing skin immunity, UV inhibits immunity in internal organs, including activation of CD8 T cells and cytotoxic T cell activity in the spleen, and memory T cell activation in the spleen and bone marrow. Neither of the chromophores responsible for UV suppression of skin immunity, DNA damage and urocanic acid, nor reactive oxygen species are involved in regulation of CD8 T cells in internal organs. Thus UVB impedes the activation and cytotoxicity of antigen-specific T cells in internal organs by mechanisms independent of suppression of skin immunity. These deleterious effects of low dose UV on skin immunity are likely to contribute to skin cancer, however UV suppression of immunity in internal organs may protect from autoimmunity. Epidemiological evidence suggests that sunlight protects from some autoimmune diseases directed towards internal organs. As UV suppression of skin and internal organ immunity appear to occur via different mechanisms, it may be possible to protect skin immunity and therefore reduce skin cancer incidence without preventing UV from reducing autoimmunity in internal organs.

WITHDRAWN: Analysis of interleukin-7 receptor-α gene single nucleotide polymorphism in Behcet's diseases - Corrected Proof

Koichiro Nakamura, Atsuko Neuchi, Tetsuya Tsuchida — 2011-03-18

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

WITHDRAWN: Preface - Corrected Proof

Masutaka Furue — 2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.003. The duplicate article has therefore been withdrawn.

WITHDRAWN: Overview of Yusho - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.004. The duplicate article has therefore been withdrawn.

WITHDRAWN: Behavior and toxic effects of PCBs and PCDFs in Yusho patients for 35 years - Corrected Proof

Yoshito Masuda, on behalf of the Study Group for Yusho — 2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.005. The duplicate article has therefore been withdrawn.

WITHDRAWN: Improvement in dioxin analysis of human blood and their concentrations in blood of Yusho patients - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.006. The duplicate article has therefore been withdrawn.

WITHDRAWN: Blood chemistry, alpha-fetoprotein and hepatitis B surface antigen in Yusho - Corrected Proof

Hiroshi Tsuji, Yasuo Ito, on behalf of the Study Group for Yusho — 2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.007. The duplicate article has therefore been withdrawn.

WITHDRAWN: Cardiac, pulmonary and renal function in Yusho patients - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.008. The duplicate article has therefore been withdrawn.

WITHDRAWN: Neurological signs and symptoms in patients with chronic PCB poisoning (Yusho accident) for more than 36 years - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.009. The duplicate article has therefore been withdrawn.

WITHDRAWN: Complete blood cell counts and blood chemistry in Yusho - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.010. The duplicate article has therefore been withdrawn.

WITHDRAWN: Ophthalmic findings in Yusho - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.018. The duplicate article has therefore been withdrawn.

WITHDRAWN: Oral mucosa and dental findings in Yusho - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.012. The duplicate article has therefore been withdrawn.

WITHDRAWN: Dermatological manifestations in Yusho: correlation between skin symptoms and blood levels of dioxins, such as polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.016. The duplicate article has therefore been withdrawn.

WITHDRAWN: Sex ratio in the children of Yusho patients - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.011. The duplicate article has therefore been withdrawn.

WITHDRAWN: Relationship of clinical symptoms and laboratory findings with blood levels of PCDFs in patients with Yusho - Corrected Proof

Yoshiyuki Kanagawa, Tomoaki Imamura, on behalf of the Study Group for Yusho — 2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.013. The duplicate article has therefore been withdrawn.

WITHDRAWN: The concepts of the new criteria for Yusho poisoning - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.014. The duplicate article has therefore been withdrawn.

WITHDRAWN: Effects of dioxins on stress-responsive systems and their relevance to toxicity - Corrected Proof

2010-07-12

The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.jdermsci.2004.12.015. The duplicate article has therefore been withdrawn.

The current status and future direction of percutaneous peptide immunization against melanoma - Corrected Proof

Naohiro Seo, Masahiro Takigawa — 2010-07-12

Summary: Dendritic cell (DC)-based tumor immunotherapy is widely known to elicit protective anti-tumor immune responses, although the safety and effectiveness have yet to be thoroughly explored. We reported that a disruption in the stratum corneum barrier resulted in enhanced permeability and alterations in the skin immune system in such a way that epidermal Langerhans cells (LCs) functioned as vigorous antigen presenters for T helper (Th) cells and cytotoxic T lymphocytes (CTLs). In both human and murine models, topical application of melanoma-associated antigen peptides onto stratum corneum barrier-disrupted skin, specifically induced tumoricidal immune responses in vivo and in vitro accompanying an increased expression of MHC and co-stimulatory molecules on LCs. In addition, for reasons of simplicity, safety and effectiveness, percutaneous peptide application has demonstrated a certain degree of feasibility in clinical approach in patients with melanoma. In the future, resolution of some of the outstanding issues concerning the selection of the most effective adjuvants in combination with barrier disruption and depletion of regulatory T (Treg) cell-mediated immune suppression would appear as essential to improve percutaneous melanoma immunotherapy.

Significance of the expression of phosphorylated-STAT3, -Akt, and -ERK1/2 in several tumors of the epidermis - Corrected Proof

2010-07-12

In general, signal transduction pathways controlling cell division and proliferation are closely correlated. Signal transducer and activator of transcription-3 (STAT3), Akt, and extracellular signal-regulated kinase1/2 (ERK1/2) are main effector molecules that are associated with cell proliferation, apoptosis, differentiation, and malignant transduction . The aims of this study are to evaluate the expression of p-STAT3, p-Akt, and p-ERK1/2 in several tumors of epidermis, and evaluate correlations between their expressions and either the tumor size or metastasis of SCC.

Tricho-rhino-phalangeal type I syndrome and mental retardation: Identification of a novel mutation in the TRPS1 gene - Corrected Proof

Luz M. Gonzalez-Huerta, Sergio A. Cuevas-Covarrubias, Olga M. Messina-Baas — 2010-07-12

After Giedion reported the first case of tricho-rhino-phalangeal syndrome (TRPS) in 1966 , three types of TRPS (I, I, III) have been described in the literature . Pear-shape nose with bulbous tip, protruding ears, sparse hair, sparse eyebrows and long flat philtrum are common features to all TRPS types. Cone-shape epiphyses are the most characteristic radiographic findings, but they are not detected before 2 years of life. The 3 types of TRPS are due to affection of the TRPS1 gene, TRPS II is a contiguous gene syndrome that differs from TRPS I by the presence of mental retardation (MR) and multiple cartilaginous exostoses (MCE). MR ranges from borderline intelligence to profound MR . Microcephaly, large ears, micrognathia and lax skin frequently are present in TRPS II . TRPS III is similar to TRPS I except by more severe shortening of phalanges and metacarpals and short stature . TRPS I is inherited as an autosomal dominant trait and is due to molecular defects in the TRPS1 gene, TRPS II apparently follows autosomal dominant inheritance, but is due to a microdeletion in 8q24.1 region . Most TRPS II patients do not show a cytogenetically detectable deletion at 8q24.1; the majority of cases with TRPS II are sporadic . TRPS III is an allelic variant due to mutations in exon 6 of the TRPS1I gene . In the present study, we describe a TRPS I patient with MR and a novel 2bp deletion in the TRPS1 gene.

Targeting TNFα rapidly reduces density of dendritic cells and macrophages in psoriatic plaques with restoration of epidermal keratinocyte differentiation - Corrected Proof

Deborah J. Marble, Kenneth B. Gordon, Brian J. Nickoloff — 2010-07-12

Summary: Background: The cytokine network theory for psoriasis postulates a key role for TNFα in mediating inflammation and altered epidermal differentiation.Objective: This study defines responses following administration of adalimumab, a TNFα inhibitor, in pre-psoriatic skin (PN) and lesional psoriatic plaques (PP) skin.Methods: PN and PP skin before and after treatment were biopsied at days 2, 7, 28 and 84 (n=6 different patients). Cryosections were immunohistochemically stained to detect TNFα and other relevant markers in epidermal and dermal compartments. Detection of apoptosis utilized antibody specific for activated caspase 3. Semiquantitative assessments and statistical analysis was performed for each staining profile.Results: TNFα+ cells were increased in PP skin. PP skin was also characterized by a four-fold increase in number of CD68+ macrophages as well as eight-fold increase in CD11c+ dermal dendritic cells (DCs) compared to PN skin. By two-color immunofluorescence staining, both CD68+ cells as well as CD11c+ cells expressed TNFα. Following initiation of adalimumab therapy, CD11c+ cells, significantly decreased in PP skin at days 7, 28, and 84, while CD68+ and CD14+ cells decreased at days 28 and 84. Other markers for DCs (CD83, CD86) showed decreases at days 7, 28, and 84. Reduction in DCs, macrophages or T cells was not accompanied by increased activated caspase 3-positive cells. When a keratinocyte terminal differentiation marker was examined, adalimumab triggered rapid restoration of loricrin expression (beginning on day 2), with loss of aberrant differentiation marker, keratin 17 (K17).Conclusion: Adalimumab impacts dermal-based immunocytes, and the epidermal compartment also responds by restoration of normal differentiation without detectable apoptosis.

Rapid changes in substance P signaling and neutral endopeptidase induced by skin-scratching stimulation in mice - Corrected Proof

Junichi Yamaoka, Seiji Kawana — 2010-07-12

Summary: Background: Skin-scratching is a commonly seen behavior in patients with pruritus which sometimes exacerbates original lesions. Substance P (SP) signaling may play a predominant role in the pathophysiology induced by skin-scratching, however, it has not been well-elucidated.Objectives: To clarify changes in SP, its receptor NK-1R and a degradating enzyme neutral endopeptidase (NEP) induced by skin-scratching stimulation in mice.Methods: After skin-scratching stimulation was given to mice, changes in SP signaling were investigated as follows. Mast cell degranulation was examined with toluidine blue staining. SP-immunoreactive nerve fibers and the expressions of NK-1R and NEP were examined with immunofluorescence. Protein contents of SP and the enzymatic activity of NEP were examined with an ELISA and a colorimetric assay, respectively.Results: After skin-scratching stimulation, mast cells significantly degranulated within several minutes. SP-immunoreactive nerve fibers disappeared immediately from sensory nerve fibers, indicating the quick secretion and the depletion of SP. Both protein contents of SP and NEP activity in skin decreased dramatically soon after skin-scratching stimulation and thereafter they returned to the basal level within a week. The expression of NK-1R was significantly upregulated in epidermal basal keratinocytes after several days, in which NEP and NK-1R were well-coexpressed. Blocking NK-1R by an NK-1R antagonist suppressed scratching-induced decreases in SP-immunoreactive nerve fibers and in NEP activity.Conclusions: The present study clarified changing patterns of factors involved in SP signaling and NEP induced by skin-scratching stimulation. These findings provide basic and useful information to understand the pathophysiology of scratching-associated pruritic skin diseases.

Flavonolignans from Silybum marianum moderate UVA-induced oxidative damage to HaCaT keratinocytes - Corrected Proof

Alena Svobodová, Adéla Zdařilová, Daniela Walterová, Jitka Vostálová — 2010-07-12

Summary: Background: UV radiation from sunlight is a very potent environmental risk factor in the pathogenesis of skin cancer. Exposure to UV light, especially the UVA part, provokes the generation of reactive oxygen species (ROS), which induce oxidative stress in exposed cells. Topical application of antioxidants is a successful strategy for protecting the skin against UV-caused oxidative damage.Objective: In this study, silybin (SB) and 2,3-dehydrosilybin (DS) (1–50μmol/l), flavonolignan components of Silybum marianum, were tested for their ability to moderate UVA-induced damage.Methods: Human keratinocytes HaCaT were used as an appropriate experimental in vitro model, to monitor the effects of SB and DS on cell viability, proliferation, intracellular ATP and GSH level, ROS generation, membrane lipid peroxidation, caspase-3 activation and DNA damage.Results: Application of the flavonolignans (1–50μmol/l) led to an increase in cell viability of irradiated (20J/cm2) HaCaT keratinocytes. SB and DS also suppressed intracellular ATP and GSH depletion, ROS production and peroxidation of membrane lipids. UVA-induced caspases-3activity/activation was suppressed by treatment with SB and DS. Lower concentrations of both compounds (10μmol/l) significantly reduced cellular DNA single strand break formation.Conclusion: Taken together, the results suggest that these flavonolignans suppress UVA-caused oxidative stress and may be useful in the treatment of UVA-induced skin damage.

Nitric oxide levels in plasma and fibroblast cultures of psoriasis vulgaris patients - Corrected Proof

Anna Zalewska, Janina Wyczółkowska, Joanna Narbutt, Anna Sysa-Jędrzejowska — 2010-07-12

Nitric oxide (NO) is an active molecule generated in many cells including fibroblasts and endothelial cells, participating in psoriatic inflammatory processes. In context of dermal vascular dilatation and increased blood flow, being characteristic features of psoriasis, the contribution of NO deserves special attention, however literature data on NO production in psoriatic plaques are inconsistent .

Indications that topical l-carnitin-l-tartrate promotes human hair growth in vivo - Corrected Proof

Kerstin Foitzik, Edo Hoting, Ulrike Heinrich, Hagen Tronnier, Ralf Paus — 2010-07-12

l-Carnitine is essential for the intramitochondrial transport of long-chain fatty acids for β-oxidation . Recently, we have shown that l-carnitine-l-tartrate (CT) is able to increase hair shaft elongation and prolong anagen by upregulation of proliferation and downregulation of apoptosis in organ-cultured human scalp hair follicles . In order to test whether CT is also able to stimulate hair growth in human scalp hair follicles (HF) in vivo, we have performed a small, double-blind, randomised, placebo-controlled observational study of topical CT administration over 6 months twice a day. Penetration of CT into the skin, employing a liposomal hair tonic (Henkel, Düsseldorf, Germany) versus a conventional hair tonic was investigated, using the BUS (bovine udder model).

Identification of proteins involved in aggregation of human dermal papilla cells by proteomics - Corrected Proof

Xia Rushan, Hao Fei, Mou Zhirong, Wu Yu-zhang — 2010-07-12

Summary: Background: The dermal papilla is a major component of hair, which signals the follicular epithelial cells to prolong the hair growth process. To date, little is known about the significance of the specific protein(s) express in the dermal papilla cells (DPC) with regard to their aggregative behaviour.Objectives: To identify proteins involved in aggregative behaviour of DPC, we comparatively analyzed the proteome of cells with and without aggregative behaviour.Methods: A series of methods were used, including two-dimensional gel electrophoresis (2-DE), PDQuest software analysis of 2-DE gels, peptide mass fingerprinting based on matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-TOF-MS), and NCBInr database searching, to separate and identify differentially expressed proteins. Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR) were used to validate the differentially expressed proteins.Results: Image analysis revealed that averages of 618±22 and 568±47 protein spots were detected in passages 3 and 10 DPC, respectively. Twenty-four differential protein spots were measured with MALDI-TOF-MS. A total of 17 spots yielded good spectra, and 15 spots matched with known proteins after database searching. Western blotting confirmed that heat shocking protein 70 was up-regulated in passage 3 DPC. Over-expression of mitochondrial ribosomal protein S7 was confirmed by RT-PCR, indicating that they are involved in aggregation of DPC through some signaling pathway.Conclusions: The clues provided by the comparative proteome strategy utilized here will shed light on molecular mechanisms of DPC in aggregative behaviour.

Associations of IL-2 and IL-4 gene polymorphisms with psoriasis in the Korean population - Corrected Proof

2010-07-12

Summary: Background: Psoriasis is association with an overexpression of T-helper cell type 1(Th1) cytokines and relative underexpression of Th2 cytokines. The cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo.Objectives: We aimed to evaluate association of cytokine genes polymorphisms with psoriasis in the Korean population.Methods: We investigated the polymorphisms of IL-2 −330, IL-4 −590, IL-4 receptor +1902, IL-10 −1082 and −819, and IFN-γ intron 1 in 114 psoriasis patients and 281 healthy normal controls in Korean.Results: IL-2 −330*G and IL-4 −590*C alleles significantly increased in psoriasis patients, especially late-onset group, compared to the control. The combined effect of IL-2 −330*G and IL-4 −590*C showed that the positive combination of IL-2 −330*G and IL-4 −590*C alleles were more significantly associated with the late-onset group of psoriasis patients than the controls.Conclusions: These results suggest that the genetic polymorphisms of IL-2 and IL-4 genes can be susceptible to psoriasis in Korean, especially late-onset psoriasis group.