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Sample records for 12-o-tetradecanoylphorbol-13-acetate-treated mouse skin

  1. Mouse model of Staphylococcus aureus skin infection.

    PubMed

    Malachowa, Natalia; Kobayashi, Scott D; Braughton, Kevin R; DeLeo, Frank R

    2013-01-01

    Bacterial skin and soft tissue infections are abundant worldwide and many are caused by Staphylococcus aureus. Indeed, S. aureus is the leading cause of skin and soft tissue infections in the USA. Here, we describe a mouse model of skin and soft tissue infection induced by subcutaneous inoculation of S. aureus. This animal model can be used to investigate a number of factors related to the pathogenesis of skin and soft tissue infections, including strain virulence and the contribution of specific bacterial molecules to disease, and it can be employed to test the potential effectiveness of antibiotic therapies or vaccine candidates.

  2. The hairless mouse in skin research

    PubMed Central

    Benavides, Fernando; Oberyszyn, Tatiana M.; VanBuskirk, Anne M.; Reeve, Vivienne E.; Kusewitt, Donna F.

    2009-01-01

    Summary The hairless (Hr) gene encodes a transcriptional co-repressor highly expressed in the mammalian skin. In the mouse, several null and hypomorphic Hr alleles have been identified resulting in hairlessness in homozygous animals, characterized by alopecia developing after a single cycle of relatively normal hair growth. Mutations in the human ortholog have also been associated with congenital alopecia. Although a variety of hairless strains have been developed, outbred SKH1 mice are the most widely used in dermatologic research. These unpigmented and immunocompetent mice allow for ready manipulation of the skin, application of topical agents, and exposure to UVR, as well as easy visualization of the cutaneous response. Wound healing, acute photobiologic responses, and skin carcinogenesis have been extensively studied in SKH1 mice and are well characterized. In addition, tumors induced in these mice resemble, both at the morphologic and molecular levels, UVR-induced skin malignancies in man. Two limitations of the SKH1 mouse in dermatologic research are the relatively uncharacterized genetic background and its outbred status, which precludes inter-individual transplantation studies. PMID:18938063

  3. Biological characteristics of mouse skin melanocytes.

    PubMed

    Shi, Zhanquan; Ji, Kaiyuan; Yang, Shanshan; Zhang, Junzhen; Yao, Jianbo; Dong, Changsheng; Fan, Ruiwen

    2016-04-01

    The objective of this research was to evaluate the optimal passage number according to the biological characteristics of mouse skin melanocytes from different passages. Skin punch biopsies harvested from the dorsal region of 2-day old mice were used to establish melanocyte cultures. The cells from passage 4, 7, 10 and 13 were collected and evaluated for their melanogenic activity. Histochemical staining for tyrosinase (TYR) activity and immunostaining for the melanocyte specific markers including S-100 antigen, TYR, tyrosinase related protein 1 (TYRP1), tyrosinase related protein 2 (TYRP2) and micropthalmia associated transcription factor (MITF) confirmed purity and melanogenic capacity of melanocytes from different passages, with better melanogenic activity of passage 10 and 13 cells being observed. Treatment of passage 13 melanocytes with α-melanocyte stimulating hormone (α-MSH) showed increased expression of MITF, TYR and TYRP2 mRNA. However, considering the TYR mRNA dramatically high expression which is the characteristics of melanoma cells, melanocytes from passage 10 was the optimal passage number for the further research. Our results demonstrate culture of pure populations of mouse melanocytes to at least 10 passages and illustrate the potential utility of passage 10 cells for studies of intrinsic and extrinsic regulation of genes controlling pigmentation and coat color in mouse.

  4. The top skin-associated genes: a comparative analysis of human and mouse skin transcriptomes.

    PubMed

    Gerber, Peter Arne; Buhren, Bettina Alexandra; Schrumpf, Holger; Homey, Bernhard; Zlotnik, Albert; Hevezi, Peter

    2014-06-01

    The mouse represents a key model system for the study of the physiology and biochemistry of skin. Comparison of skin between mouse and human is critical for interpretation and application of data from mouse experiments to human disease. Here, we review the current knowledge on structure and immunology of mouse and human skin. Moreover, we present a systematic comparison of human and mouse skin transcriptomes. To this end, we have recently used a genome-wide database of human gene expression to identify genes highly expressed in skin, with no, or limited expression elsewhere - human skin-associated genes (hSAGs). Analysis of our set of hSAGs allowed us to generate a comprehensive molecular characterization of healthy human skin. Here, we used a similar database to generate a list of mouse skin-associated genes (mSAGs). A comparative analysis between the top human (n=666) and mouse (n=873) skin-associated genes (SAGs) revealed a total of only 30.2% identity between the two lists. The majority of shared genes encode proteins that participate in structural and barrier functions. Analysis of the top functional annotation terms revealed an overlap for morphogenesis, cell adhesion, structure, and signal transduction. The results of this analysis, discussed in the context of published data, illustrate the diversity between the molecular make up of skin of both species and grants a probable explanation, why results generated in murine in vivo models often fail to translate into the human.

  5. Diffusion of (2-/sup 14/C)diazepam across hairless mouse skin and human skin

    SciTech Connect

    Koch, R.L.; Palicharla, P.; Groves, M.J.

    1987-05-01

    The objectives of this study were to investigate the absorption of diazepam applied topically to the hairless mouse in vivo and to determine the diffusion of diazepam across isolated hairless mouse skin and human skin. (/sup 14/C)Diazepam was readily absorbed after topical administration to the intact hairless mouse, a total of 75.8% of the /sup 14/C-label applied being recovered in urine and feces. Diazepam was found to diffuse across human and hairless mouse skin unchanged in experiments with twin-chambered diffusion cells. The variation in diffusion rate or the flux for both human and mouse tissues was greater among specimens than between duplicate or triplicate trials for a single specimen. Fluxes for mouse skin (stratum corneum, epidermis, and dermis) were greater than for human skin (stratum corneum and epidermis): 0.35-0.61 microgram/cm2/h for mouse skin vs 0.24-0.42 microgram/cm2/h for human skin. The permeability coefficients for mouse skin ranged from 1.4-2.4 X 10(-2)cm/h compared with 0.8-1.4 X 10(-2)cm/h for human skin. Although human stratum corneum is almost twice the thickness of that of the hairless mouse, the diffusion coefficients for human skin were 3-12 times greater (0.76-3.31 X 10(-6) cm2/h for human skin vs 0.12-0.27 X 10(-6) cm2/h for hairless mouse) because of a shorter lag time for diffusion across human skin. These differences between the diffusion coefficients and diffusion rates (or permeability coefficients) suggest that the presence of the dermis may present some barrier properties. In vitro the dermis may require complete saturation before the diazepam can be detected in the receiving chamber.

  6. Hydrocortisone Diffusion Through Synthetic Membrane, Mouse Skin, and Epiderm™ Cultured Skin

    PubMed Central

    Christensen, John Mark; Chuong, Monica Chang; Le, Hang; Pham, Loan; Bendas, Ehab

    2011-01-01

    Objectives The penetration of hydrocortisone (HC) from six topical over-the-counter products along with one prescription cream through cultured normal human-derived epidermal keratinocytes (Epiderm™), mouse skin and synthetic nylon membrane was performed as well as the effect hydrating the skin by pre-washing was explored using the Upright Franz Cell. Method and Results Permeation of HC through EpiDerm™, mouse skin and synthetic membrane was highest with the topical HC gel formulation with prewash treatment of the membranes among seven products evaluated, 198 ± 32 µg/cm2, 746.32 ± 12.43 µg/cm2, and 1882 ± 395.18 µg/cm2, respectively. Pre-washing to hydrate the skin enhanced HC penetration through EpiDerm™ and mouse skin. The 24-hour HC released from topical gel with prewash treatment was 198.495 ± 32 µg/cm2 and 746.32 ± 12.43 µg/cm2 while without prewash, the 24-h HC released from topical gel was 67.2 ± 7.41 µg/cm2 and 653.43 ± 85.62 µg/cm2 though EpiDerm™ and mouse skin, respectively. HC penetration through synthetic membrane was ten times greater than through mouse skin and EpiDerm™. Generally, the shape, pattern, and rank order of HC diffusion from each commercial product was similar through each membrane. PMID:21572515

  7. Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis.

    PubMed

    Budunova, I V; Carbajal, S; Kang, H; Viaje, A; Slaga, T J

    1997-03-01

    Glucocorticoids are the most potent inhibitors of tumor promotion in mouse skin, when applied with a promoting agent at the early stages of promotion. However, established skin papillomas become resistant to growth inhibition by glucocorticoids. Glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Here we present data on GR expression and function in mouse papillomas and squamous cell carcinomas. Tumors were produced in SENCAR mice by a 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate two-stage protocol. In early papillomas (after 15-20 wk of promotion), northern blotting revealed a decrease in the GR mRNA level that was confirmed by a binding assay. However, in late papillomas (after 30-40 wk of promotion), and especially in squamous cell carcinomas, the level of GR in both assays was similar to or higher than the GR level in normal epidermis. To test the functional capability of GR in tumors, we compared the effect of the synthetic glucocorticoid fluocinolone acetonide (FA) on keratinocyte proliferation and on expression of glucocorticoid-responsive genes in normal epidermis, hyperplastic skin surrounding tumors, and mouse skin papillomas. FA strongly inhibited DNA synthesis in keratinocytes in normal skin and tumor-surrounding skin but had no effect on DNA synthesis in papillomas. In addition, FA strongly induced metallothionein 1 expression and inhibited connexin 26 expression in skin but did not affect expression of these genes in tumors. These data suggest that alteration of both the expression and function of GR may be an important mechanism of tumor promotion in skin.

  8. Jute batching oil: a tumor promoter on mouse skin

    SciTech Connect

    Mehrotra, N.K.; Kumar, S.; Agarwal, R.; Antony, M.

    1987-02-01

    A mineral oil essentially used in the jute industry for the batching of jute fibers, and earlier reported to be nontumorigenic on mouse skin, has been found to be a tumor promoter following a two-stage mouse-skin bioassay protocol. The types of tumors developed after initiation with a single dose of urethane or 3-methylcholanthrene (subcutaneously), followed by repeated skin painting with jute batching oil (JBO) included benign papillomas, keratoacanthomas, and fibrosarcomas. Chemical analysis of this oil indicated the total aromatic content was 11.71% and the amount of fluoranthene, pyrene, chrysene, and triphenylene was in the range of 192.54 to 227.79 mg/kg in the test sample. The underlying biochemical mechanism for the tumor-promoting effect of JBO seemed to operate through a different pathway rather than involving the induction of cytochrome-dependent monoxygenase and N-demethylase activities in the tissue.

  9. Recovery and Cultivation of Keratinocytes From Shipped Mouse Skin.

    PubMed

    Yang, Hsin-Ya; La, Thi Dinh; Gurenko, Zhanna; Steenhuis, Pieter; Liu, Wei; Isseroff, R Rivkah

    2015-02-01

    Murine keratinocyte culture from neonatal skin is an important tool for studying the functional role of specific genes in epithelial biology. However, when the transgenic animal is only available in a geographically distant local, obtaining viable keratinocytes can be problematic. A method for transferring the isolated murine skin from collaborating labs could decrease the cost of shipping live animals, and would allow the efficient use of the tissues from the transgenic animals. Here we optimized shipping conditions and characterized the cells retrieved and cultured from mouse skin shipped for 48 h at 0 °C. The cultured keratinocytes from the control, non-shipped skin and the 2-day shipped skin were 43.6 +/- 7.8% viable, doubled every 2 days, and expressed comparable amounts of heat shock proteins and CD29/integrin beta-1. However, under the same shipping conditions, the 3-day shipped tissue failed to establish colonies in the culture. Therefore, this 2-day shipping technique allows the transfer mouse skin from distant locations with recovery of viable, propagatable keratinocytes, facilitating long-distance collaborations.

  10. Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

    SciTech Connect

    Mancuso, Mariateresa; Leonardi, Simona; Giardullo, Paola; Pasquali, Emanuela; Tanori, Mirella; De Stefano, Ilaria; Casciati, Arianna; Naus, Christian C.; Pazzaglia, Simonetta; Saran, Anna

    2013-08-01

    Purpose: To investigate the tissue dependence in transmission of abscopal radiation signals and their oncogenic consequences in a radiosensitive mouse model and to explore the involvement of gap junction intercellular communication (GJIC) in mediating radiation tumorigenesis in off-target mouse skin. Methods and Materials: Patched1 heterozygous (Ptch1{sup +/−}) mice were irradiated at postnatal day 2 (P2) with 10 Gy of x-rays. Individual lead cylinders were used to protect the anterior two-thirds of the body, whereas the hindmost part was directly exposed to radiation. To test the role of GJICs and their major constituent connexin43 (Cx43), crosses between Ptch1{sup +/−} and Cx43{sup +/−} mice were similarly irradiated. These mouse groups were monitored for their lifetime, and skin basal cell carcinomas (BCCs) were counted and recorded. Early responses to DNA damage - Double Strand Breaks (DSBs) and apoptosis - were also evaluated in shielded and directly irradiated skin areas. Results: We report abscopal tumor induction in the shielded skin of Ptch1{sup +/−} mice after partial-body irradiation. Endpoints were induction of early nodular BCC-like tumors and macroscopic infiltrative BCCs. Abscopal tumorigenesis was significantly modulated by Cx43 status, namely, Cx43 reduction was associated with decreased levels of DNA damage and oncogenesis in out-of-field skin, suggesting a key role of GJIC in transmission of oncogenic radiation signals to unhit skin. Conclusions: Our results further characterize the nature of abscopal responses and the implications they have on pathologic processes in different tissues, including their possible underlying mechanistic bases.

  11. Notch1 functions as a tumor suppressor in mouse skin.

    PubMed

    Nicolas, Michael; Wolfer, Anita; Raj, Kenneth; Kummer, J Alain; Mill, Pleasantine; van Noort, Mascha; Hui, Chi-chung; Clevers, Hans; Dotto, G Paolo; Radtke, Freddy

    2003-03-01

    Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

  12. Intravital insights in skin wound healing using the mouse dorsal skin fold chamber.

    PubMed

    Sorg, Heiko; Krueger, Christian; Vollmar, Brigitte

    2007-12-01

    The skin fold chamber is one of the most accepted animal models for studying the microcirculation both in health and disease. Here we describe for the first time the alternative use of the skin fold chamber in mice for intravital microscopic investigation of skin regeneration after creating a full dermal thickness wound. The dorsal skin fold chamber was implanted in hairless SKH1-hr mice and a full dermal thickness wound (area approximately 4 mm2) was created. By means of intravital fluorescence microscopy, the kinetics of wound healing were analyzed for 12 days post wounding with assessment of epithelialization and nutritive perfusion. The morphology of the regenerating skin was characterized by hematoxylin-eosin histology and immunohistochemistry for proliferation and microvessel density. The model allows the continuous visualization of wound closure with complete epithelialization at day 12. Furthermore, a sola cutis se reficientis could be described by an inner circular ring of vessels at the wound margin surrounded by outer radial passing vessels. Inner circular vessels presented initially with large diameters and matured towards diameters of less than 15 microm for conversion into radial spreading outer vessels. Furthermore, wound healing showed all diverse core issues of skin repair. In summary, we were able to establish a model for the analysis of microcirculation in the healing skin of the mouse. This versatile model allows distinct analysis of new vessel formation and maturation in regenerating skin as well as evaluation of skin healing under different pathologic conditions.

  13. In vitro percutaneous absorption in mouse skin: influence of skin appendages

    SciTech Connect

    Kao, J.; Hall, J.; Helman, G.

    1988-06-15

    Skin appendages are often envisaged as channels that bypass the stratum corneum barrier and are generally thought to facilitate the dermal absorption of topical agents. However, the significance of this transappendageal pathway in percutaneous absorption remains to be assessed experimentally. With the use of a skin organ culture penetration chamber system, the influence of skin appendages on the in vitro permeation of topically applied benzo(a)pyrene and testosterone (5 micrograms/2 cm2) was examined in skin preparations from both haired and hairless mice. Haired mice examined included the C57BL6, C3H, DBA2, Balbc, and Sencar strains and the hairless mice were the HRS and SKH. In all mouse strains examined, the overall permeation of testosterone (greater than 65% of applied dose) 16 hr following in vitro topical application was greater than that of benzo(a)pyrene (less than 10%). No strain differences were observed with respect to the percutaneous permeation of testosterone; however, percutaneous permeation of benzo(a)pyrene in the haired mice (7-10% of applied dose) was higher than that in the hairless mice (2%). In an in-house derived mouse strain which showed three phenotypic variants due to hair densities, the permeability to both compounds was highest in the skin of the haired phenotype (testosterone 67%, benzo(a)pyrene 7%), lowest in the hairless phenotype (35 and 1%, respectively) and intermediate in the fuzzy-haired animal (57 and 3%, respectively). Examination by fluorescence microscopy of cryosections of skin, prepared 1 hr after topical benzo(a)pyrene, showed areas of intense fluorescence deep within the nonfluorescing dermis of skin from the haired phenotype. These fluorescent areas were correlated with follicular ducts and sebaceous glands.

  14. Skin Carcinogenesis Studies Using Mouse Models with Altered Polyamines

    PubMed Central

    Nowotarski, Shannon L; Feith, David J; Shantz, Lisa M

    2015-01-01

    Nonmelanoma skin cancer (NMSC) is a major health concern worldwide. With increasing numbers in high-risk groups such as organ transplant recipients and patients taking photosensitizing medications, the incidence of NMSC continues to rise. Mouse models of NMSC allow us to better understand the molecular signaling cascades involved in skin tumor development in order to identify novel therapeutic strategies. Here we review the models designed to determine the role of the polyamines in NMSC development and maintenance. Elevated polyamines are absolutely required for tumor growth, and dysregulation of their biosynthetic and catabolic enzymes has been observed in NMSC. Studies using mice with genetic alterations in epidermal polyamines suggest that they play key roles in tumor promotion and epithelial cell survival pathways, and recent clinical trials indicate that pharmacological inhibitors of polyamine metabolism show promise in individuals at high risk for NMSC. PMID:26380554

  15. The nude mouse model for the study of human skin disorders.

    PubMed

    Gilhar, A; Etzioni, A

    1994-01-01

    Normal human skin grafted onto the nude mouse can be maintained without any signs of rejection throughout the life-span of the animal. Indeed, the nude mouse model is a powerful tool for understanding the pathological process of the skin. Until now many skin diseases such as psoriasis, cutaneous lupus, pemphigus and vitiligo have been looked at using the nude mouse model, which has helped to clarify the role of the various factors involved.

  16. Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex

    PubMed Central

    Guo, Yanan; Dreier, John R.; Cao, Juxiang; Du, Heng; Granter, Scott R.; Kwiatkowski, David J.

    2016-01-01

    Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis. They did develop a prominent skin phenotype with marked thickening of the dermis with accumulation of mast cells, that was minimally responsive to systemic rapamycin therapy, and was quite different from the pathology seen in human TSC skin lesions. Recombination and loss of Tsc1 was demonstrated in skin fibroblasts in vivo and in cultured skin fibroblasts. Loss of Tsc1 in fibroblasts in mice does not lead to a model of angiomyolipoma or lymphangioleiomyomatosis. PMID:27907099

  17. Evaluation of seven sunscreens on hairless mouse skin

    SciTech Connect

    Walter, J.F.

    1981-01-01

    The ability of seven sunscreens to protect against ultraviolet (UV)--induced inhibition of epidermal DNA synthesis was evaluated in vivo using a hairless mouse model. There were statistically significant differences among sunscreens in their ability to prevent UV-B (290 to 320 nm) inhibition of DNA synthesis. The protective factor (PF) of a sunscreen was arbitrarily defined as the ratio of the dose required to inhibit DNA synthesis by 50% with and without a sunscreen. The following PF values were determined: Coppertone 4, 4.4; Sundown Extra Protection, 8.4; Supershade 15, 21.0; Eclipse 15, 22.2; Blockout 15, 22.4; and Bain de Soleil 15, 27.6. Zinc oxide ointment protected against any significant suppression of DNA synthesis at all UV-B doses used. There was a relatively good correlation between the PF and the sun protection factor (SPF) claimed for each sunscreen by the manufacturer. However, the PF values determined in mouse skin were generally higher than the SPF values measured in human skin. Further studies are needed to determine if sunscreen substantivity (resistance to removal by water) can be evaluated by this technique.

  18. Radiation effect in mouse skin: Dose fractionation and wound healing

    SciTech Connect

    Gorodetsky, R.; Mou, X.D.; Fisher, D.R.; Taylor, J.M.; Withers, H.R. )

    1990-05-01

    Radiation induced dermal injury was measured by the gain in the physical strength of healing wounds in mouse skin. A sigmoid dose response for the inhibition of wound healing 14 days after surgery was found for single doses of X rays. The sparing of dermal damage from fractionation of the X-ray dose was quantified in terms of the alpha/beta ratio in the linear-quadratic (LQ) model, at a wide range of doses per fraction reaching as low as about 1 Gy. The fit and the appropriateness of the LQ model for the skin wound healing assay was examined with the use of the Fe-plot in which inverse total dose is plotted versus dose per fraction for wound strength isoeffects. The alpha/beta ratio of the skin was about 2.5 Gy (95% confidence of less than +/- 1 Gy) and was appropriate over a dose range of 1 Gy to about 8 Gy. The low alpha/beta value is typical for a late responding tissue. This assay, therefore, has the advantage of measuring and forecasting late radiation responses of the dermis within a short time after irradiation.

  19. Preventive effect of antihistaminics on mouse skin photosensitization with hematoporphyrin derivative

    NASA Astrophysics Data System (ADS)

    Fu, Nai-wu; Yan, Li-xue

    1993-03-01

    Beta-carotene 100 mg/kg per day or vitamin C 50 mg/kg per day was administered orally for two days and did not prevent mouse skin photosensitization caused by hematoporphyrin derivative (HpD). However, (beta) -carotene 100 mg/kg per day administered intramuscularly for two days prevented mouse skin reaction. Cimetidine and benadryl 10 mg/kg per day, P.O.X 2, effectively prevented mouse skin reaction. This suggests histamine may be involved in skin photoreaction induced by HpD.

  20. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    PubMed Central

    Xia, Xiaojun; Park, Eunmi; Fischer, Susan M.; Hu, Yinling

    2013-01-01

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside. PMID:24216703

  1. Uptake of topically applied 5-aminolevulinic acid and production of protoporphyrin IX in normal mouse skin: dependence on skin temperature.

    PubMed

    Juzenas, P; Sørensen, R; Iani, V; Moan, J

    1999-04-01

    The temperature dependence of the uptake phase of 5-aminolevulinic acid (ALA) and the following production phase of protoporphyrin IX (PpIX) in normal mouse skin was investigated. A cream containing 20% ALA was topically applied on the skin for 10 min. The amount of ALA-induced PpIX was evaluated by measuring the fluorescence of PpIX from the treated skin. No measurable amount of PpIX was found in the skin immediately after 10 min application of ALA. The penetration of ALA into the skin was almost temperature independent while the following production of PpIX was found to be a strongly temperature-dependent process. Practically no PpIX was formed in the skin as long as skin temperature was kept low (12 degrees C).

  2. Quantifying levels of p53 mutation in mouse skin tumors.

    PubMed

    Verkler, Tracie L; Couch, Letha H; Howard, Paul C; Parsons, Barbara L

    2005-06-01

    Allele-specific competitive blocker PCR (ACB-PCR) amplification and quantification was developed for mouse p53 codon 270 CGT-->TGT base substitution and codon 244/245 AAC/CGC-->AAT/TGC tandem mutation. PCR products corresponding to p53 mutant and wild-type DNA sequences were generated. These DNAs were mixed in known proportions to construct samples with defined mutant fractions and the allele-specific detection of each mutation was systematically optimized. Each assay was used to analyze eight simulated solar light (SSL)-induced tumors. By analyzing mutant fraction (MF) standards in parallel with PCR products generated from tumor samples, p53 mutants could be quantified as subpopulations within the tumors. All eight tumors contained detectable levels of p53 codon 270 CGT-->TGT mutation. Three tumors had p53 MFs between 10(-4) and 10(-3). Five tumors had p53 MFs between 10(-3) and 10(-2). None of the eight mouse skin tumors had measurable levels of p53 codon 244/245 tandem mutation. Frequent detection of p53 codon 270 CGT-->TGT mutation provides additional evidence that a pyrimidine dinucleotide overlapping a methylated CpG site (Pyr(me)CG) is a susceptible target for SSL-induced mutagenesis. The absence of p53 codon 244/245 mutation in tumors may be explained by its mutant p53 phenotype and/or indicate that this site is not methylated. These initial results indicate that p53 codon 270 CGT-->TGT mutation may be a sensitive biomarker for SSL- or UV-induced mutagenesis. This mutational endpoint may be useful for evaluating the co-carcinogenicity of compounds administered in combination with UV or SSL.

  3. Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin.

    PubMed

    Al-Khalili, Mohammad; Meidan, Victor M; Michniak, Bozena B

    2003-01-01

    The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm2 resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel resulted in a synergistic effect when combined with iontophoresis. Menthol was the most active enhancer, and when combined with iontophoresis it was possible to deliver 10 mg/cm2/day of buspirone hydrochloride.

  4. Localization of the defect in skin diseases analyzed in the human skin graft-nude mouse model.

    PubMed

    Briggaman, R A

    1980-01-01

    Human skin can be grown away from its donor for prolonged periods as grafts on congenitally athymic "nude" mice. This system has been used to analyze the defect in several skin diseases, specifically to localize the site of the defect to the skin itself or to the epidermal or dermal components of the skin. In order to validate the use of the nude mouse human skin graft system in the analysis of skin defects, we have demonstrated that a systemic metabolic defect which involves the skin, namely essential fatty acid deficiency, can be differentiated from a defect residing primarily in the skin itself. Skin-marker systems have been developed for use with the nude mouse-human skin graft model to document the identity of human skin grafts and epidermal and dermal components of the grafts after prolonged periods of growth on the nude athymic mice. Y-body, a small fluorescent segment of the Y-chromosome seen in interphase cells, is used as a sex marker and serves to distinguish sex differences between the graft and the mouse recipient or between skin components of the graft. The ABH "blood-group" antigens are present on differentiated epidermal cell surfaces and identify the grafted epidermis according to the blood groups of the donor. In previous studies, lamellar ichthyosis was shown to be well maintained after prolonged periods of growth on nude athymic mice, indicating that the defect in this disease resides in the skin itself. Recombinant grafts composed of normal and lamellar ichthyosis epidermis and dermis further localize the defect to lamellar ichthyosis epidermis. Psoriasis is well maintained on the nude mouse-skin graft model. The epidermal hyperplasia and hyperproliferative epidermal cell kinetics of psoriasis are manifested in the grafts of active psoriasis maintained for prolonged periods on the nude mice, but the inflammatory component of psoriasis is absent. Recombinant graft studies utilizing normal and psoriatic epidermis and dermis demonstrate psoriasis

  5. Epidermal proliferation of nude mouse skin, pig skin, and pig skin grafts. Failure of nude mouse skin to respond to the tumor promoter 12- O-tetradecanoyl phorbol 13-acetate

    PubMed Central

    1980-01-01

    Human skin transplanted to nude mice offers a possible experimental system for the study of normal epidermal proliferation and differentiation, and for their pathological counterparts. Crucial to the development of such a system is the demonstration that such grafts retain the responsive features of donor skin. To document that donor proliferative characteristics are maintained in the grafts, a comparative analysis of agents that induce proliferation was made on skin of mice homozygous and heterozygous for nude, on pig skin, and on pig skin transplanted onto nude mice. A wave of epidermal proliferation could be induced in pig skin and pig skin grafted onto nude mice, but not in nude mouse skin after the topical application of 10 ng 12-O- tetradecanoyl phorbol 13-acetate (TPA). A 10-fold greater concentration of TPA or 5% croton oil induced proliferation in all species of epidermis studied. Mice, heterozygous for nude, showed a normal response to 10 ng TPA, suggesting that the ability to respond to TPA may be related, in part, to a recessive genetic trait. Nude mouse skin transplanted to a heterozygous littermate capable of responding to 10 ng TPA does not respond. These observations argue that: the graft retains its donor proliferative characteristics when transplanted to the nude, and the inability of the nude mouse to respond to lower doses of TPA may be related to absorption, the nude gene(s), or an inherent threshold to response. The lack of response to the promoter TPA provides a plausible explanation for the decreased incidence of tumors arising in nude mice during two-stage carcinogenesis experiments. PMID:7000965

  6. Tumorigenesis of diesel exhaust, gasoline exhaust, and related emission extracts on SENCAR mouse skin

    SciTech Connect

    Nesnow, S; Triplett, L L; Slaga, T J

    1980-01-01

    The tumorigenicity of diesel exhaust particulate emissions was examined using a sensitive mouse skin tumorigenesis model (SENCAR). The tumorigenic potency of particulate emissions from diesel, gasoline, and related emission sources was compared.

  7. Photoeffects of near ultraviolet light upon a polycyclic aromatic hydrocarbon exposed to mouse skin microsomes

    SciTech Connect

    Peirano, W.B.

    1991-01-01

    Near ultraviolet (UV) light has been reported to both enhance and inhibit the tumor incidence in mice dermally exposed to benzo(a)pyrene (BaP) or polycyclic aromatic hydrocarbon (PAH) mixtures. Near UV light interacts with PAHs producing a variety of oxygenated products such as phenols, endoperoxides and quinones. However, little is known about BaP products formed from near UV irradiation of BaP-exposed mouse skin. Therefore, [sup 14]C-BaP was incubated with 3-methylcholanthrene (3-MC) induced C[sub 3]H/HeJ and DBA/2J mouse skin microsomes with or without a 365 nm light source. The results indicated that the concurrent 365 nm light irradiation of induced mouse skin microsomes and BaP greatly enhanced the total conversion of BaP to its products, approximately 3-fold for the C[sub 3]H/HeJ and approximately 7-fold for the DBA/2J mouse microsomes, compared to the induced mouse skin microsomes and BaP alone. HPLC analyses of organic extracts indicated a more than additive enhancement of the formation of most of the individual cochromatographed BaP metabolites due to the combined interaction of 365 nm light with BaP and skin microsomes. Similar interactions were observed using benz(a)anthracene (BaA) in this system. These data show that near UV light alters the metabolic profile of PAHs produced by mouse skin microsomes.

  8. Characterization of the serotoninergic system in the C57BL/6 mouse skin.

    PubMed

    Slominski, Andrzej; Pisarchik, Alexander; Semak, Igor; Sweatman, Trevor; Wortsman, Jacobo

    2003-08-01

    We showed expression of the tryptophan hydroxylase gene and of tryptophan hydroxylase protein immunoreactivity in mouse skin and skin cells. Extracts from skin and melanocyte samples acetylated serotonin to N-acetylserotonin and tryptamine to N-acetyltryptamine. A different enzyme from arylalkylamine N-acetyltransferase mediated this reaction, as this gene was defective in the C57BL6 mouse, coding predominantly for a protein without enzymatic activity. Serotonin (but not tryptamine) acetylation varied according to hair cycle phase and anatomic location. Serotonin was also metabolized to 5-hydroxytryptophol and 5-hydroxyindole acetic acid, probably through stepwise transformation catalyzed by monoamine oxidase, aldehyde dehydrogenase and aldehyde reductase. Activity of the melatonin-forming enzyme hydroxyindole-O-methyltransferase was notably below detectable levels in all samples of mouse corporal skin, although it was detectable at low levels in the ears and in Cloudman melanoma (derived from the DBA/2 J mouse strain). In conclusion, mouse skin has the molecular and biochemical apparatus necessary to produce and metabolize serotonin and N-acetylserotonin, and its activity is determined by topography, physiological status of the skin, cell type and mouse strain.

  9. The nature of the chromophore responsible for naturally occurring fluorescence in mouse skin.

    PubMed

    Weagle, G; Paterson, P E; Kennedy, J; Pottier, R

    1988-11-01

    Normal mouse skin has a prominent fluorescence peak at 674 nm. Fluorescence emission and fluorescence excitation spectroscopy, carried out both in vitro and in vivo, led to the conclusion that the chromophore(s) responsible for this naturally occurring fluorescence is/are pheophorbide a and/or pheophytin a, degradation products of chlorophyll a that are derived from the mouse food.

  10. Skin fragility in the wild-derived, inbred mouse strain Mus pahari/EiJ.

    PubMed

    Herbert Pratt, C; Potter, Christopher S; Kuiper, Raoul V; Karst, Son Yong; Dadras, Soheil S; Roopenian, Derry C; Sundberg, John P

    2017-02-01

    Mus pahari is a wild-derived, inbred mouse strain. M. pahari colony managers observed fragility of this strain's skin resulting in separation of tail skin from the mouse if handled incorrectly. Tail skin tension testing of M. pahari resulted in significantly lowered force threshold for caudal skin rupture and loss in comparison to closely related inbred mouse species and subspecies and even more than a model for junctional epidermolysis bullosa. Histologically, the tail skin separated at the subdermal level with the dermis firmly attached to the epidermis, excluding the epidermolysis bullosa complex of diseases. The dermal collagen bundles were abnormally thickened and branched. Elastin fiber deposition was focally altered in the dermis adjacent to the hair follicle. Collagens present in the skin could not be differentiated between the species in protein gels following digestion with pepsin. Together these data suggest that M. pahari have altered extracellular matrix development resulting in separation of the skin below the level of the dermis with moderate force similar to the African spiny mouse (Acomys spp.).

  11. Optical clearing assisted confocal microscopy of ex vivo transgenic mouse skin

    NASA Astrophysics Data System (ADS)

    Song, Eunjoo; Ahn, YoonJoon; Ahn, Jinhyo; Ahn, Soyeon; Kim, Changhwan; Choi, Sanghoon; Boutilier, Richard Martin; Lee, Yongjoong; Kim, Pilhan; Lee, Ho

    2015-10-01

    We examined the optical clearing assisted confocal microscopy of the transgenic mouse skin. The pinna and dorsal skin were imaged with a confocal microscope after the application of glycerol and FocusClear. In case of the glycerol-treated pinna, the clearing was minimal due to the inefficient permeability. However, the imaging depth was improved when the pinna was treated with FocusClear. In case of dorsal skin, we were able to image deeply to the subcutaneous connective tissue with both agents. Various skin structures such as the vessel, epithelium cells, cartilage, dermal cells, and hair follicles were clearly imaged.

  12. In vitro and in vivo transdermal delivery capacity of quantum dots through mouse skin

    NASA Astrophysics Data System (ADS)

    Chu, Maoquan; Wu, Qiang; Wang, Jiaxu; Hou, Shengke; Miao, Yi; Peng, Jinliang; Sun, Ye

    2007-11-01

    CdTe quantum dots (QDs) with red fluorescence have been used to study their transdermal delivery capacity through mouse skin. The results showed that the QDs could permeate through skin, either separated from or still attached to live mice. Although the fluorescence emitted by the QDs could only be found in the skin and muscle cells located under the mouse skins coated with QDs, an inductive coupled plasma atomic emission spectrometry (ICP-AES) study indicated that the main organs, such as the heart, liver, spleen, lung, kidney and brain, all contained a significant quantity of Cd atoms. Moreover, these Cd atoms could remain in vivo for at least one week. As a control, the concentration of Cd atoms in normal mice not coated with QDs was very low.

  13. Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin

    PubMed Central

    Kumar, Amit; Li, Xinran; Sandoval, Michael A; Rodriguez, B Leticia; Sloat, Brian R; Cui, Zhengrong

    2011-01-01

    Background: The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection. Methods and results: It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection. Conclusion: Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection. PMID:21753877

  14. Preparation of Single-cell Suspensions for Cytofluorimetric Analysis from Different Mouse Skin Regions.

    PubMed

    Broggi, Achille; Cigni, Clara; Zanoni, Ivan; Granucci, Francesca

    2016-04-20

    The skin is a barrier organ that interacts with the external environment. Being continuously exposed to potential microbial invasion, the dermis and epidermis home a variety of immune cells in both homeostatic and inflammatory conditions. Tools to obtain skin cell release for cytofluorimetric analyses are, therefore, very useful in order to study the complex network of immune cells residing in the skin and their response to microbial stimuli. Here, we describe an efficient methodology for the digestion of mouse skin to rapidly and efficiently obtain single-cell suspensions. This protocol allows maintenance of maximum cell viability without compromising surface antigen expression. We also describe how to take and digest skin samples from different anatomical locations, such as the ear, trunk, tail, and footpad. The obtained suspensions are then stained and analyzed by flow cytometry to discriminate between different leukocyte populations.

  15. Protective effects of black rice bran against chemically-induced inflammation of mouse skin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We investigated the inhibitory effects of black rice (cv. LK1-3-6-12-1-1) bran against 12-O-tetradecanolylphorbol-13-acetate (TPA)-induced skin edema and 2,4-dinitroflurobenzene (DNFB)-induced allergic contact dermatitis (ACD) in inflammatory mouse models. We also determined the effects of the bran...

  16. The optical properties of mouse skin in the visible and near infrared spectral regions.

    PubMed

    Sabino, Caetano P; Deana, Alessandro M; Yoshimura, Tania M; da Silva, Daniela F T; França, Cristiane M; Hamblin, Michael R; Ribeiro, Martha S

    2016-07-01

    Visible and near-infrared radiation is now widely employed in health science and technology. Pre-clinical trials are still essential to allow appropriate translation of optical methods into clinical practice. Our results stress the importance of considering the mouse strain and gender when planning pre-clinical experiments that depend on light-skin interactions. Here, we evaluated the optical properties of depilated albino and pigmented mouse skin using reproducible methods to determine parameters that have wide applicability in biomedical optics. Light penetration depth (δ), absorption (μa), reduced scattering (μ's) and reduced attenuation (μ't) coefficients were calculated using the Kubelka-Munk model of photon transport and spectrophotometric measurements. Within a broad wavelength coverage (400-1400nm), the main optical tissue interactions of visible and near infrared radiation could be inferred. Histological analysis was performed to correlate the findings with tissue composition and structure. Disperse melanin granules present in depilated pigmented mouse skin were shown to be irrelevant for light absorption. Gender mostly affected optical properties in the visible range due to variations in blood and abundance of dense connective tissue. On the other hand, mouse strains could produce more variations in the hydration level of skin, leading to changes in absorption in the infrared spectral region. A spectral region of minimal light attenuation, commonly referred as the "optical window", was observed between 600 and 1350nm.

  17. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  18. Development of a Bioengineered Skin-Humanized Mouse Model for Psoriasis

    PubMed Central

    Guerrero-Aspizua, Sara; García, Marta; Murillas, Rodolfo; Retamosa, Luisa; Illera, Nuria; Duarte, Blanca; Holguín, Almudena; Puig, Susana; Hernández, Maria Isabel; Meana, Alvaro; Jorcano, Jose Luis; Larcher, Fernando; Carretero, Marta; Del Río, Marcela

    2010-01-01

    Over the past few years, whole skin xenotransplantation models that mimic different aspects of psoriasis have become available. However, these models are strongly constrained by the lack of skin donor availability and homogeneity. We present in this study a bioengineering-based skin-humanized mouse model for psoriasis, either in an autologous version using samples derived from psoriatic patients or, more importantly, in an allogeneic context, starting from skin biopsies and blood samples from unrelated healthy donors. After engraftment, the regenerated human skin presents the typical architecture of normal human skin but, in both cases, immunological reconstitution through intradermal injection in the regenerated skin using in vitro-differentiated T1 subpopulations as well as recombinant IL-17 and IL-22 Th17 cytokines, together with removal of the stratum corneum barrier by a mild abrasive treatment, leads to the rapid conversion of the skin into a bona fide psoriatic phenotype. Major hallmarks of psoriasis were confirmed by the evaluation of specific epidermal differentiation and proliferation markers as well as the mesenchymal milieu, including angiogenesis and infiltrate. Our bioengineered skin-based system represents a robust platform to reliably assess the molecular and cellular mechanisms underlying the complex interdependence between epidermal cells and the immune system. The system may also prove suitable to assess preclinical studies that test the efficacy of novel therapeutic treatments and to predict individual patient response to therapy. PMID:20971736

  19. Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin

    PubMed Central

    Tong, Tao; Kim, Nahyun; Park, Taesun

    2015-01-01

    We observed that oleuropein, the main constituent of the leaves and unprocessed olive drupes of Olea europaea, protected mice from high-fat diet-induced adiposity by up-regulation of genes involved in Wnt10b-mediated signaling in adipose tissue. The activation of Wnt/β-catenin pathway is also well established to positively regulate the anagen phase of hair growth cycle in mice skin. Methodology and Principal Findings Oleuropein promoted cultured human follicle dermal papilla cell proliferation and induced LEF1 and Cyc-D1 mRNA expression and β-catenin protein expression in dermal papilla cells. Nuclear accumulation of β-catenin in dermal papilla cells was observed after oleuropein treatment. Topical application of oleuropein (0.4 mg/mouse/day) to C57BL/6N mice accelerated the hair-growth induction and increased the size of hair follicles in telogenic mouse skin. The oleuropein-treated mouse skin showed substantial upregulation of Wnt10b, FZDR1, LRP5, LEF1, Cyc-D1, IGF-1, KGF, HGF, and VEGF mRNA expression and β-catenin protein expression. Conclusions and Significance These results demonstrate that topical oleuroepin administration induced anagenic hair growth in telogenic C57BL/6N mouse skin. The hair-growth promoting effect of oleuropein in mice appeared to be associated with the stimulation of the Wnt10b/β-catenin signaling pathway and the upregulation of IGF-1, KGF, HGF, and VEGF gene expression in mouse skin tissue. PMID:26060936

  20. Influence of the hair cycle on the thickness of mouse skin

    SciTech Connect

    Hansen, L.S.; Coggle, J.E.; Wells, J.; Charles, M.W.

    1984-12-01

    The data on mouse skin thickness reported here was prompted by the need to know the true position of basal cells of the epidermis and hair follicles as these are important cells at risk for a variety of skin reactions including carcinogenesis following exposure to radiation. There is little reliable data in the literature and most previous reports have ignored the shrinkage of skin that occurs because of its natural elasticity. The values determined for mouse flank skin in telogen--the resting phase of the hair cycle for the different skin layers--are epidermis 10 micron, corium 250 micron, adipose layer 150 micron, and hair follicle depth 150 micron. Three days after chemical depilation which triggers the hair follicles into active cycle (anagen) the epidermis doubles in thickness, remains at this value for 7 days, and then gradually returns to telogen values by day 18. The corium and adipose layers also increase significantly to reach approximately 390 micron and approximately 260 micron, respectively, by day 10 and then return to control values from day 15 onward. The change in hair follicles depths are more dramatic with active follicle basal cells reaching approximately 450-550 micron into the adipose layer between days 7 and 15. One important finding is that chemical depilation does not affect the telogen thickness of skin-the teleogen values for the epidermis and dermis immediately prior to and immediately after depilation were similar to those 23 days later at the beginning of the next telogen phase.

  1. Metabolic conversion of 12-O-tetradecanoylphorbol-13-acetate in adult and newborn mouse skin and mouse liver microsomes.

    PubMed

    Berry, D L; Bracken, W M; Fischer, S M; Viaje, A; Slaga, T J

    1978-08-01

    Tritiated 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to adult mouse skin; at specified time intervals the mice were killed, and the labeled phorbol was extracted and subjected to separation and quantitation by high-pressure liquid chromatography. After 24 hr, TPA comprised greater than 96% of the recovered label from the skin, and its apparent half-life was 17.8 hr. Pretreatment of adult skin with TPA for 4 weeks before treatment with labeled TPA resulted in an increase in the clearance rate of TPA from the skin. Skin from newborn mice was capable of converting TPA into monoesters and phorbol, but the clearance rate in the adult was about 12 times more rapid than it was in the newborn. Epidermal homogenates converted TPA into 12-O-tetradecanoylphorbol, phorbol-13-acetate, and phorbol. Hepatic homogenates were able to convert TPA to monoesters and phorbol at rates 14 to 15 times faster than were epidermal homogenates. Attempts to isolate any previously undescribed metabolites of TPA by use of liver homogenates were unsuccessful, and mixed-function oxidation did not contribute to the metabolism of TPA. From inhibitor studies it was judged that esterases were implicated in the conversion of TPA to monoesters and phorbol. The results support the hypothesis that the tumor-promoting activity of TPA is directly related to its concentration in a specific tissue and that conversion of TPA to an active metabolite probably does not occur.

  2. Histology and Ultrastructure of Transitional Changes in Skin Morphology in the Juvenile and Adult Four-Striped Mouse (Rhabdomys pumilio)

    PubMed Central

    Stewart, Eranée; Ajao, Moyosore Salihu

    2013-01-01

    The four-striped mouse has a grey to brown coloured coat with four characteristic dark stripes interspersed with three lighter stripes running along its back. The histological differences in the skin of the juvenile and adult mouse were investigated by Haematoxylin and Eosin and Masson Trichrome staining, while melanocytes in the skin were studied through melanin-specific Ferro-ferricyanide staining. The ultrastructure of the juvenile skin, hair follicles, and melanocytes was also explored. In both the juvenile and adult four-striped mouse, pigment-containing cells were observed in the dermis and were homogeneously dispersed throughout this layer. Apart from these cells, the histology of the skin of the adult four-striped mouse was similar to normal mammalian skin. In the juvenile four-striped mouse, abundant hair follicles of varying sizes were observed in the dermis and hypodermis, while hair follicles of similar size were only present in the dermis of adult four-striped mouse. Ultrastructural analysis of juvenile hair follicles revealed that the arrangement and differentiation of cellular layers were typical of a mammal. This study therefore provides unique transition pattern in the four-striped mouse skin morphology different from the textbook description of the normal mammalian skin. PMID:24288469

  3. Histology and ultrastructure of transitional changes in skin morphology in the juvenile and adult four-striped mouse (Rhabdomys pumilio).

    PubMed

    Stewart, Eranée; Ajao, Moyosore Salihu; Ihunwo, Amadi Ogonda

    2013-01-01

    The four-striped mouse has a grey to brown coloured coat with four characteristic dark stripes interspersed with three lighter stripes running along its back. The histological differences in the skin of the juvenile and adult mouse were investigated by Haematoxylin and Eosin and Masson Trichrome staining, while melanocytes in the skin were studied through melanin-specific Ferro-ferricyanide staining. The ultrastructure of the juvenile skin, hair follicles, and melanocytes was also explored. In both the juvenile and adult four-striped mouse, pigment-containing cells were observed in the dermis and were homogeneously dispersed throughout this layer. Apart from these cells, the histology of the skin of the adult four-striped mouse was similar to normal mammalian skin. In the juvenile four-striped mouse, abundant hair follicles of varying sizes were observed in the dermis and hypodermis, while hair follicles of similar size were only present in the dermis of adult four-striped mouse. Ultrastructural analysis of juvenile hair follicles revealed that the arrangement and differentiation of cellular layers were typical of a mammal. This study therefore provides unique transition pattern in the four-striped mouse skin morphology different from the textbook description of the normal mammalian skin.

  4. SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice.

    PubMed Central

    Slaga, T J

    1986-01-01

    The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters. PMID:3096709

  5. SENCAR mouse skin tumorigenesis model versus other strains and stocks of mice

    SciTech Connect

    Slaga, T.J.

    1986-09-01

    The SENCAR mouse stock was selectively bred for eight generations for sensitivity to skin tumor induction by the two-stage tumorigenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The SENCAR mouse was derived by crossing Charles River CD-1 mice with skin-tumor-sensitive mice (STS). The SENCAR mice are much more sensitive to both DMBA tumor initiation and TPA tumor promotion than CD-1, BALB/c, and DBA/2 mice. An even greater difference in the sensitivity to two-stage skin tumorigenesis is apparent between SENCAR and C57BL/6 mice when using DMBA-TPA treatment. However, the SENCAR and C57BL/6 mice have a similar tumor response to DMBA-benzoyl peroxide treatment, suggesting that TPA is not an effective promoter in C57BL/6 mice. The DBA/2 mice respond in a similar manner to the SENCAR mice when using N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-TPA treatment. The SENCAR mouse model provides a good dose-response relationship for many carcinogens used as tumor initiators and for many compounds used as tumor promoter. When compared to other stocks and strains of mice, the SENCAR mouse has one of the largest data bases for carcinogens and promoters.

  6. Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

    PubMed Central

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E.; Heath, Emma; Smedley, Damian P.; Estabel, Jeanne; Sunter, David; DiTommaso, Tia; White, Jacqueline K.; Ramirez-Solis, Ramiro; Smyth, Ian; Steel, Karen P.; Watt, Fiona M.

    2014-01-01

    Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. PMID:24721909

  7. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

    SciTech Connect

    Jain, Anil K.; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J.; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

    2015-05-15

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. - Highlights: • Silibinin treatment attenuated nitrogen mustard (NM)-induced skin injury. • Silibinin affects pathways associated with DNA damage, inflammation and vesication. • The efficacy of silibinin could also be associated with oxidative stress. • These results support testing and optimization of

  8. Defining the clonal dynamics leading to mouse skin tumour initiation

    PubMed Central

    Sánchez-Danés, Adriana; Hannezo, Edouard; Larsimont, Jean-Christophe; Liagre, Mélanie; Youssef, Khalil Kass; Simons, Benjamin D; Blanpain, Cédric

    2016-01-01

    The changes that occur in cell dynamics following oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the impact of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, were competent to initiate tumour formation upon oncogenic hedgehog signalling. Interestingly, this difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase of symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours. Our work reveals that the capacity of oncogene-targeted cells to induce tumour formation is not only dependent on their long-term survival and expansion, but also on the specific clonal dynamics of the cancer cell of origin. PMID:27459053

  9. High-power femtosecond-terahertz pulse induces a wound response in mouse skin

    NASA Astrophysics Data System (ADS)

    Kim, Kyu-Tae; Park, Jaehun; Jo, Sung Jin; Jung, Seonghoon; Kwon, Oh Sang; Gallerano, Gian Piero; Park, Woong-Yang; Park, Gun-Sik

    2013-08-01

    Terahertz (THz) technology has emerged for biomedical applications such as scanning, molecular spectroscopy, and medical imaging. Although a thorough assessment to predict potential concerns has to precede before practical utilization of THz source, the biological effect of THz radiation is not yet fully understood with scant related investigations. Here, we applied a femtosecond-terahertz (fs-THz) pulse to mouse skin to evaluate non-thermal effects of THz radiation. Analysis of the genome-wide expression profile in fs-THz-irradiated skin indicated that wound responses were predominantly mediated by transforming growth factor-beta (TGF-β) signaling pathways. We validated NFκB1- and Smad3/4-mediated transcriptional activation in fs-THz-irradiated skin by chromatin immunoprecipitation assay. Repeated fs-THz radiation delayed the closure of mouse skin punch wounds due to up-regulation of TGF-β. These findings suggest that fs-THz radiation initiate a wound-like signal in skin with increased expression of TGF-β and activation of its downstream target genes, which perturbs the wound healing process in vivo.

  10. Effects of housing conditions on the development of wet skin lesions in the NOA mouse.

    PubMed

    Kondo, Taizo; Kondo, Toshio; Shiomoto, Yasuhisa; Momii, Akira

    2005-04-01

    The effects of housing on the onset time and prevalence of wet skin lesions were investigated in NOA mice, which spontaneously develop these lesions at a high rate. Wet skin lesions developed earliest in mice that were housed individually. For mice that were housed in groups, the lesions developed earlier in mice with non-littermate group housing than in mice with littermate group housing. The prevalence of lesions was in the following order: individual housing > non-littermate group housing > littermate group housing. These results suggest that socio-psychological factors are involved in the etiology of wet skin lesions in the NOA mouse. Under individual housing conditions, two other novel characters of the NOA mouse were also observed, specifically, development of dry skin and wet skin lesions at the tail root. These characteristics developed early and with high prevalence and were easily observed on external examination. Therefore, these novel characteristics observed in NOA mice are potential markers of the psychological state of the animals.

  11. Gas chromatography-mass spectrometry analysis of effects of dietary fish oil on total fatty acid composition in mouse skin

    PubMed Central

    Wang, Peiru; Sun, Min; Ren, Jianwei; Djuric, Zora; Fisher, Gary J.; Wang, Xiuli; Li, Yong

    2017-01-01

    Altering the fatty acid (FA) composition in the skin by dietary fish oil could provide therapeutic benefits. Although it has been shown that fish oil supplementation enhances EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) abundance in the skin, comprehensive skin FA profiling is needed. We established a gas chromatography-mass spectrometry method, which allows precise quantification of FA profile using small (<24 mm2 for mice and <12 mm2 for humans) skin specimens that can be readily obtained from live mice and humans. We determined mouse skin FA composition after 2, 4 and 8 weeks of consuming a control diet or a diet supplemented with fish oil. Fish oil markedly enhanced EPA and DHA in mouse skin within 2 weeks, and this increase plateaued after 4 weeks. The FA composition in mouse skin was different from that of serum, indicating that skin has homeostatic control of FA metabolism. Mice fed the control diet designed to simulate Western human diet displayed similar skin FA composition as that of humans. The present study presents a validated method for FA quantification that is needed to investigate the mechanisms of actions of dietary treatments in both mouse and human skin. PMID:28195161

  12. Curcumin Stimulates the Antioxidant Mechanisms in Mouse Skin Exposed to Fractionated γ-Irradiation.

    PubMed

    Jagetia, Ganesh Chandra; Rajanikant, Golgod Krishnamurthy

    2015-01-13

    Fractionated irradiation is one of the important radiotherapy regimens to treat different types of neoplasia. Despite of the immense therapeutic gains accrued by delivering fractionated irradiation to tumors, the radiation burden on skin increases significantly. Low doses of irradiation to skin adversely affect its molecular and metabolic status. The use of antioxidant/s may help to alleviate the radiation-induced changes in the skin and allow delivering a higher dose of radiation to attain better therapeutic gains. Curcumin is an antioxidant and a free radical scavenging dietary supplement, commonly used as a flavoring agent in curries. Therefore, the effect of 100 mg/kg body weight curcumin was studied on the antioxidant status of mice skin exposed to a total dose of 10, 20 and 40 Gy γ-radiation below the rib cage delivered as a single fraction of 2 Gy per day for 5, 10 or 20 days. Skin biopsies from both the curcumin treated or untreated irradiated groups were collected for the biochemical estimations at various post-irradiation times. The irradiation of animals caused a dose dependent decline in the glutathione concentration, glutathione peroxidase, and superoxide dismutase activities and increased the lipid peroxidation in the irradiated skin. Curcumin treatment before irradiation resulted in a significant rise in the glutathione concentration and activities of both the glutathione peroxidase and superoxide dismutase enzymes in mouse skin, whereas lipid peroxidation declined significantly. The present study indicates that curcumin treatment increased the antioxidant status of mouse exposed to different doses of fractionated γ-radiation.

  13. Topical application of ochratoxin A causes DNA damage and tumor initiation in mouse skin.

    PubMed

    Kumar, Rahul; Ansari, Kausar M; Chaudhari, Bhushan P; Dhawan, Alok; Dwivedi, Premendra D; Jain, Swatantra K; Das, Mukul

    2012-01-01

    Skin cancer is one of the most common forms of cancer and 2-3 million new cases are being diagnosed globally each year. Along with UV rays, environmental pollutants/chemicals including mycotoxins, contaminants of various foods and feed stuffs, could be one of the aetiological factors of skin cancer. In the present study, we evaluated the DNA damaging potential and dermal carcinogenicity of a mycotoxin, ochratoxin A (OTA), with the rationale that dermal exposure to OTA in workers may occur during their involvement in pre and post harvest stages of agriculture. A single topical application of OTA (20-80 µg/mouse) resulted in significant DNA damage along with elevated γ-H2AX level in skin. Alteration in oxidative stress markers such as lipid peroxidation, protein carbonyl, glutathione content and antioxidant enzymes was observed in a dose (20-80 µg/mouse) and time-dependent (12-72 h) manner. The oxidative stress was further emphasized by the suppression of Nrf2 translocation to nucleus following a single topical application of OTA (80 µg/mouse) after 24 h. OTA (80 µg/mouse) application for 12-72 h caused significant enhancement in- (a) reactive oxygen species generation, (b) activation of ERK1/2, p38 and JNK MAPKs, (c) cell cycle arrest at G0/G1 phase (37-67%), (d) induction of apoptosis (2.0-11.0 fold), (e) expression of p53, p21/waf1, (f) Bax/Bcl-2 ratio, (g) cytochrome c level, (h) activities of caspase 9 (1.2-1.8 fold) and 3 (1.7-2.2 fold) as well as poly ADP ribose polymerase cleavage. In a two-stage mouse skin tumorigenesis protocol, it was observed that a single topical application of OTA (80 µg/mouse) followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 24 week leads to tumor formation. These results suggest that OTA has skin tumor initiating property which may be related to oxidative stress, MAPKs signaling and DNA damage.

  14. Induction of megakaryocytic colony-stimulating activity in mouse skin by inflammatory agents and tumor promoters

    SciTech Connect

    Clark, D.A.; Dessypris, E.N.; Koury, M.J.

    1987-03-01

    The production of megakaryocytic colony-stimulating activity (MEG-CSA) was assayed in acetic acid extracts of skin from mice topically treated with inflammatory and tumor-promoting agents. A rapid induction of MEG-CSA was found in skin treated both with phorbol 12-myristate 13-acetate (PMA), a strong tumor promoter, and with mezerein, a weak tumor promoter, but no induction was found in untreated skin. The time course of induction of MEG-CSA following treatment of skin with PMA or mezerein was very similar to that previously demonstrated for the induction of granulocyte-macrophage colony-stimulating activity in mouse skin by these agents. The induced MEG-CSA was found in both the epidermis and the dermis. Pretreatment of the skin with US -methasone abrogated the MEG-CSA induction. The cell number response curve suggests that the MEG-CSA acts directly on the progenitor cells of the megakaryocyte colonies. That topical administration of diterpene esters results in the rapid, local induction of MEG-CSA which can be blocked by US -methasone pretreatment suggests a mechanism for the thrombocytosis associated with some inflammatory states. The indirect action in which diterpene esters induce in certain cells the production or release of growth regulatory factors for other cell types may also aid in understanding their carcinogenic properties.

  15. Suppressive function of RKTG on chemical carcinogen-induced skin carcinogenesis in mouse.

    PubMed

    Xie, Xiaoduo; Zhang, Yixuan; Jiang, Yuhui; Liu, Weizhong; Ma, Hong; Wang, Zhenzhen; Chen, Yan

    2008-08-01

    Raf kinase trapping to Golgi (RKTG) is a newly characterized negative regulator of the Ras-Raf-MEK-ERK signaling pathway via sequestrating Raf-1 to the Golgi apparatus. However, little is known about the physiological functions of RKTG in mitogenic pathway and carcinogenesis. Here, we describe a suppressive role of RKTG in skin carcinogenesis by analyzing chemical carcinogen-induced tumorigenesis. Epidermis hyperplasia and proliferation are increased in RKTG-deficient mice (RKTG(-/-)) after acute treatment with 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Using a two-stage DMBA/TPA carcinogenesis protocol on mouse skin, the number and size of papillomas are increased in RKTG(-/-) mice, accompanied by shortened tumor latency and enhanced keratinocyte proliferation. The regression of the carcinogen-induced tumors is also prolonged in RKTG(-/-) mice. Consistently, the levels of Raf-1 and extracellular signal-regulated kinase phosphorylation in primary keratinocytes as well as skin tumors are elevated when RKTG is disrupted. Collectively, our results indicate that RKTG has a suppressive activity in chemical carcinogen-induced mitogenesis and tumor formation in mouse skin.

  16. Ultraviolet light induction of skin carcinoma in the mouse; influence of cAMP modifying agents.

    PubMed

    Zajdela, F; Latarjet, R

    1978-01-01

    A short review of pathogenic factors in U.V. light skin carcinogenesis in the mouse is presented. Caffeine and theophylline applied locally during U.V. irradiation caused a 50 percent reduction of skin tumour induction in Swiss mice. These two chemicals are inhibitors of DNA postreplication repair, but they also raise the intracellular level of cyclic AMP by inhibiting cAMP phosphodiesterase with, as a consequence, a possible slowing down of cellular growth. Control experiments using three different chemicals capable of raising the cAMP level in epidermal cells gave negative results. These experimental data are compatible with our original hypothesis according to which production of skin cancers by U.V. radiation is in same way related to DNA repair which helps the cell to survive but allows or favours the occurrence of errors in cellular DNA.

  17. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin.

    PubMed

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2015-05-15

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants.

  18. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

    PubMed Central

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2015-01-01

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51% reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. PMID:25791923

  19. Biology of human skin transplanted to the nude mouse: I. Response to agents which modify epidermal proliferation.

    PubMed

    Krueger, G G; Shelby, J

    1981-06-01

    To accept human skin transplanted to the congenitally athymic (nude) mouse as a system to study human skin and its physiologic and pathologic states, it must be demonstrated that skin so maintained retains its function as a biologic unit. We have found that responses of grafted human skin and nude mouse skin to various agents differ. This difference in response has been utilized to assess barrier function and proliferative capacity of human skin grafts. Human skin grafts undergo a proliferative response when 10 ng of the tumor promoter, 12-O-tetradecanoyl phorbol 13-acetate (TPA) is applied. Nudes do not respond to this dose. Increasing the dose to 100 ng of TPA evokes a response in both. However, only in the human skin grafts can this response be blocked with betamethasone valerate (BV). In that human skin grafts do not take on their hosts' responsiveness, and the response of domestic pig skin to these agents before and after grafting is identical, the conclusion is reached that human skin appears to retain its inherent biologic unit function. The data also demonstrate some of the potential of this system to study kinetics of the epidermis of human skin.

  20. Connexin expression in epidermal cell lines from SENCAR mouse skin tumors.

    PubMed

    Budunova, I V; Carbajal, S; Viaje, A; Slaga, T J

    1996-03-01

    Alteration of gap-junctional intercellular communication (GJIC) has long been proposed to be involved in carcinogenesis. Previously, we reported that the level of gap junctional intercellular communication in mouse skin carcinoma cell lines is significantly lower than in papilloma cell lines and normal mouse keratinocytes Klann et al., Cancer Res 49:699-705, 1989). Here, we present data on expression of the gap-junctional protein connexins (Cx) 26, Cx31.1, and Cx43 in a comprehensive panel of keratinocyte cell lines representing different stages of mouse skin carcinogenesis and the effect of different conditions of propagation on Cx phenotype. Northern and western blot analyses and immunostaining showed that all cell lines studied in vitro expressed Cx43 but most did not express Cx31.1 or Cx26. The abundance of Cx43 expression on plasma membranes correlated well with the level of GJIC. In vivo expression of Cx43 and Cx26 was strongly increased. Whereas none of tumorigenic cell lines expressed Cx26 gap junctions in culture, those growing as tumors in nude mice began to express Cx26 protein. The comparison of Cx expression on the keratinocyte membranes in three different groups of tumors (papillomas and squamous cell and spindle cell carcinomas) clearly revealed that the abundance of Cx43 and Cx26 expression directly correlated with the level of tumor differentiation. All studied tumors were Cx31.1 negative. These results suggest that both Cx expression and gap-junction permeability are gradually reduced during the tumor progression stage of mouse skin carcinogenesis.

  1. Dose-Dependent Onset of Regenerative Program in Neutron Irradiated Mouse Skin

    PubMed Central

    Artibani, Mara; Kobos, Katarzyna; Colautti, Paolo; Negri, Rodolfo; Amendola, Roberto

    2011-01-01

    Background Tissue response to irradiation is not easily recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons. Methodology/Principal Findings To monitor general response to irradiation and individual animal to animal variation, we performed gene and protein expression analysis with both pooled and individual mouse samples. A high-throughput gene expression analysis, by DNA oligonucleotide microarray was done with three months old C57Bl/6 mice irradiated with 0.2 and 1 Gy of mono-energetic 14 MeV neutron compared to sham irradiated controls. The results on 440 irradiation modulated genes, partially validated by quantitative real time RT-PCR, showed a dose-dependent up-regulation of a sub-class of keratin and keratin associated proteins, and members of the S100 family of Ca2+-binding proteins. Immunohistochemistry confirmed mRNA expression data enabled mapping of protein expression. Interestingly, proteins up-regulated in thickening epidermis: keratin 6 and S100A8 showed the most significant up-regulation and the least mouse-to-mouse variation following 0.2 Gy irradiation, in a concerted effort toward skin tissue regeneration. Conversely, mice irradiated at 1 Gy showed most evidence of apoptosis (Caspase-3 and TUNEL staining) and most 8-oxo-G accumulation at 24 h post-irradiation. Moreover, no cell proliferation accompanied 1 Gy exposure as shown by Ki67 immunohistochemistry. Conclusions/Significance The dose-dependent differential gene expression at the tissue level following in vivo exposure to neutron radiation is reminiscent of the onset of re-epithelialization and wound healing and depends on the proportion of cells carrying multiple chromosomal lesions in the entire tissue. Thus, this study presents in vivo evidence of a skin regenerative program exerted independently from DNA repair

  2. SNEV(Prp19/PSO4) deficiency increases PUVA-induced senescence in mouse skin.

    PubMed

    Monteforte, Rossella; Beilhack, Georg F; Grausenburger, Reinhard; Mayerhofer, Benjamin; Bittner, Reginald; Grillari-Voglauer, Regina; Sibilia, Maria; Dellago, Hanna; Tschachler, Erwin; Gruber, Florian; Grillari, Johannes

    2016-03-01

    Senescent cells accumulate during ageing in various tissues and contribute to organismal ageing. However, factors that are involved in the induction of senescence in vivo are still not well understood. SNEV(P) (rp19/) (PSO) (4) is a multifaceted protein, known to be involved in DNA damage repair and senescence, albeit only in vitro. In this study, we used heterozygous SNEV(+/-) mice (SNEV-knockout results in early embryonic lethality) and wild-type littermate controls as a model to elucidate the role of SNEV(P) (rp19/) (PSO) (4) in DNA damage repair and senescence in vivo. We performed PUVA treatment as model system for potently inducing cellular senescence, consisting of 8-methoxypsoralen in combination with UVA on mouse skin to induce DNA damage and premature skin ageing. We show that SNEV(P) (rp19/) (PSO) (4) expression decreases during organismal ageing, while p16, a marker of ageing in vivo, increases. In response to PUVA treatment, we observed in the skin of both SNEV(P) (rp19/) (PSO) (4) and wild-type mice an increase in γ-H2AX levels, a DNA damage marker. In old SNEV(P) (rp19/) (PSO) (4) mice, this increase is accompanied by reduced epidermis thickening and increase in p16 and collagenase levels. Thus, the DNA damage response occurring in the mouse skin upon PUVA treatment is dependent on SNEV(P) (rp19/) (PSO) (4) expression and lower levels of SNEV(P) (rp19/) (PSO) (4) , as in old SNEV(+/-) mice, result in increase in cellular senescence and acceleration of premature skin ageing.

  3. Photoreactivation of ultraviolet radiation-induced pyrimidine dimers in neonatal BALB/c mouse skin

    SciTech Connect

    Ananthaswamy, H.N.; Fisher, M.S.

    1981-05-01

    The numbers of ultraviolet light (uv)-induced pyrimidine dimers in the DNA of neonatal BALB/c mouse skin were measured by assessing the sensitivity of the DNA to Micrococcus luteus uv endonuclease. Irradiation of neonatal BALB/c mice with FS40 sunlamps caused a dose-dependent induction of endonuclease-sensitive sites (pyrimidine dimers) in DNA extracted from back skin. Exposure of these uv-irradiated neonatal mice to photoreactivating (PR) light (cool white fluorescent lamp and incandescent lamp) caused a reduction in the number of pyrimidine dimers in the DNA, as revealed by a shift in low-molecular-weight DNA to high-molecular-weight DNA. In contrast, DNA profiles of the skin of either uv-irradiated mice or uv-irradiated mice kept in the dark for the same duration as those exposed to PR light did not show a loss of uv-induced endonuclease-sensitive sites. Furthermore, reversing the order of treatment, i.e., administering PR light first and then uv, did not produce a reduction in pyrimidine dimers. These results demonstrate that PR or uv-induced pyrimidine dimers occurs in neonatal BALB/c mouse skin. The optimal wavelength range for in vivo PR appears to be in the visible region of the spectrum (greater than 400 nm). Although dimer formation could be detected in both dermis and epidermis, PR occurred only in the dermis. Furthermore, the PR phenomenon could not be detected in the skin of adult mice from the same inbred strain.

  4. Compressive viscoelasticity of freshly excised mouse skin is dependent on specimen thickness, strain level and rate.

    PubMed

    Wang, Yuxiang; Marshall, Kara L; Baba, Yoshichika; Lumpkin, Ellen A; Gerling, Gregory J

    2015-01-01

    Although the skin's mechanical properties are well characterized in tension, little work has been done in compression. Here, the viscoelastic properties of a population of mouse skin specimens (139 samples from 36 mice, aged 5 to 34 weeks) were characterized upon varying specimen thickness, as well as strain level and rate. Over the population, we observed the skin's viscoelasticity to be quite variable, yet found systematic correlation of residual stress ratio with skin thickness and strain, and of relaxation time constants with strain rates. In particular, as specimen thickness ranged from 211 to 671 μm, we observed significant variation in both quasi-linear viscoelasticity (QLV) parameters, the relaxation time constant (τ1 = 0.19 ± 0.10 s) and steady-state residual stress ratio (G∞ = 0.28 ± 0.13). Moreover, when τ1 was decoupled and fixed, we observed that G∞ positively correlated with skin thickness. Second, as steady-state stretch was increased (λ∞ from 0.22 to 0.81), we observed significant variation in both QLV parameters (τ1 = 0.26 ± 0.14 s, G∞ = 0.47 ± 0.17), and when τ1 was fixed, G∞ positively correlated with stretch level. Third, as strain rate was increased from 0.06 to 22.88 s-1, the median time constant τ1 varied from 1.90 to 0.31 s, and thereby negatively correlated with strain rate. These findings indicate that the natural range of specimen thickness, as well as experimental controls of compression level and rate, significantly influence measurements of skin viscoelasticity.

  5. Imaging the electric field associated with mouse and human skin wounds

    PubMed Central

    Nuccitelli, Richard; Nuccitelli, Pamela; Ramlatchan, Samdeo; Sanger, Richard; Smith, Peter J.S.

    2011-01-01

    We have developed a noninvasive instrument called the bioelectric field imager (BFI) for mapping the electric field between the epidermis and the stratum corneum near wounds in both mouse and human skin. Rather than touching the skin, the BFI vibrates a small metal probe with a displacement of 180 μm in air above the skin to detect the surface potential of the epidermis through capacitative coupling. Here we describe our first application of the BFI measuring the electric field between the stratum corneum and epidermis at the margin of skin wounds in mice. We measured an electric field of 177 ± 14 (61) mV/mm immediately upon wounding and the field lines pointed away from the wound in all directions around it. Because the wound current flows immediately upon wounding, this is the first signal indicating skin damage. This electric field is generated at the outer surface of the epidermis by the outward flow of the current of injury. An equal and opposite current must flow within the multilayered epidermis to generate an intraepidermal field with the negative pole at the wound site. Because the current flowing within the multilayered epidermis is spread over a larger area, the current density and subsequent E field generated in that region is expected to be smaller than that measured by the BFI beneath the stratum corneum. The field beneath the stratum corneum typically remained in the 150–200 mV/mm range for 3 days and then began to decline over the next few days, falling to zero once wound healing was complete. The mean wound field strength decreased by 64 ± 7% following the application of the sodium channel blocker, amiloride, to the skin near the wound and increased by 82 ± 21% following the application of the Cl– channel activator, prostaglandin E2. PMID:18471262

  6. Expression of the Integrin-Linked Kinase (ILK) in Mouse Skin

    PubMed Central

    Xie, Wen; Li, Fugang; Kudlow, Jeffrey E.; Wu, Chuanyue

    1998-01-01

    Integrin-linked kinase (ILK) is a newly identified serine/threonine protein kinase implicated in integrin signaling. To investigate the functions of ILK in vivo, we have analyzed the expression and regulation of ILK in the skin, in which proper control of cell-extracellular matrix interactions and cell proliferation is essential for its normal development and homeostasis. We report here that ILK is abundantly expressed throughout the extracellular matrix-rich dermis. ILK mRNA was also detected in the hair follicles and the basal cells of the interfollicular epidermis. However, ILK expression is lost in the suprabasal layers of keratinocytes that are undergoing terminal differentiation. PINCH, an ILK-binding protein, exhibited a similar expression pattern in the skin. Recent studies have indicated that erbB-2, a member of the epidermal growth factor receptor family, plays a pivotal role in epidermal growth, differentiation, and hair follicle morphogenesis. Using a transgenic mouse system in which an activated erbB-2 is overexpressed in the epidermis, we show that ILK expression is regulated by erbB-2. The in vivo expression and regulation patterns of ILK, together with its biochemical activities, suggest an important role of ILK in coordinating the integrin signaling pathways and the growth factor signaling pathways in the development of the skin and the pathogenesis of skin diseases. PMID:9708797

  7. Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis.

    PubMed

    Tho, L M; Libertini, S; Rampling, R; Sansom, O; Gillespie, D A

    2012-03-15

    Chk1 is a key regulator of DNA damage checkpoint responses and genome stability in eukaryotes. To better understand how checkpoint proficiency relates to cancer development, we investigated the effects of genetic ablation of Chk1 in the mouse skin on tumors induced by chemical carcinogens. We found that homozygous deletion of Chk1 immediately before carcinogen exposure strongly suppressed benign tumor (papilloma) formation, and that the few, small lesions that formed in the ablated skin always retained Chk1 expression. Remarkably, Chk1 deletion rapidly triggered spontaneous cell proliferation, γ-H2AX staining and apoptosis within the hair follicle, a principal site of origin for carcinogen-induced tumors. At later times, the ablated skin was progressively repopulated by non-recombined Chk1-expressing cells and ultimately normal sensitivity to tumor induction was restored when carcinogen treatment was delayed. In marked contrast, papillomas formed normally in Chk1 hemizygous skin but showed an increased propensity to progress to carcinoma. Thus, complete loss of Chk1 is incompatible with epithelial tumorigenesis, whereas partial loss of function (haploinsufficiency) fosters benign malignant tumor progression.

  8. Potent suppressive activity of chlorophyll a and b from green tea (Camellia sinensis) against tumor promotion in mouse skin.

    PubMed

    Higashi-Okai, K; Okai, Y

    1998-09-01

    Potent antigenotoxic and anti-tumor promoting activities of chlorophyll a from green tea (camellia sinensis) have been shown using in vitro cell culture experiments (Okai Y. et al. (1996) Mutation Res., 370, 11-17). In the present study, the authors analyzed in vivo effects of chlorophyll a and b from green tea on tumor promotion in mouse skin in the following ways. 1. When chlorophyll a and b from green tea were applied before each treatment by a tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on BALB/c mouse skin initiated by 7, 12-dimethylbenz [a] an-thracene (DMBA), they caused significant suppression in a dose-dependent manner against BALB/c mouse skin tumorigenesis. 2. Chlorophyll a and b showed significant suppressive effects against TPA-induced inflammatory reaction such as edema formation in BALB/c mouse ear skin in a dose-dependent fashion. These results suggest that chlorophyll a and b possess potent suppressive activities against tumor promotion in mouse skin.

  9. Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway

    SciTech Connect

    Mishra, Sakshi; Tripathi, Anurag; Chaudhari, Bhushan P.; Dwivedi, Premendra D.; Pandey, Haushila P.; Das, Mukul

    2014-09-01

    Several toxicological manifestations of deoxynivalenol (DON), a mycotoxin, are well documented; however, dermal toxicity is not yet explored. The effect of topical application of DON to mice was studied using markers of skin proliferation, inflammation and tumor promotion. Single topical application of DON (84–672 nmol/mouse) significantly enhanced dermal hyperplasia and skin edema. DON (336 and 672 nmol) caused significant enhancement in [{sup 3}H]-thymidine uptake in DNA along with increased myeloperoxidase and ornithine decarboxylase activities, suggesting tissue inflammation and cell proliferation. Furthermore, DON (168 nmol) caused enhanced expression of RAS, and phosphorylation of PI3K/Akt, ERK, JNK and p38 MAPKs. DON exposure also showed activation of transcription factors, c-fos, c-jun and NF-κB along with phosphorylation of IkBα. Enhanced phosphorylation of NF-κB by DON caused over expression of target proteins, COX-2, cyclin D1 and iNOS in skin. Though a single topical application of DMBA followed by twice weekly application of DON (84 and 168 nmol) showed no tumorigenesis after 24 weeks, however, histopathological studies suggested hyperplasia of the epidermis and hypertrophy of hair follicles. Interestingly, intestine was also found to be affected as enlarged Peyer's patches were observed, suggesting inflammatory effects which were supported by elevation of inflammatory cytokines after 24 weeks of topical application of DON. These results suggest that DON induced cell proliferation in mouse skin is through the activation of MAPK signaling pathway involving transcription factors NFκB and AP-1, further leading to transcriptional activation of downstream target proteins c-fos, c-jun, cyclin D1, iNOS and COX-2 which might be responsible for its inflammatory potential. - Highlights: • Topical application of DON enhanced epidermal inflammation and cell proliferation. • DON follows PI3K/Akt/MAPK signaling cascade, with activation of AP-1 and NF

  10. In Vivo Imaging of Human and Mouse Skin with a Handheld Dual-Axis Confocal Fluorescence Microscope

    PubMed Central

    Gonzalez-Gonzalez, Emilio; Mandella, Michael J.; Kino, Gordon S.; Solgaard, Olav; Leake, Devin; Kaspar, Roger L.; Oro, Anthony; Contag, Christopher H.

    2013-01-01

    Advancing molecular therapies for the treatment of skin diseases will require the development of new tools that can reveal spatiotemporal changes in the microanatomy of the skin and associate these changes with the presence of the therapeutic agent. For this purpose, we evaluated a handheld dual-axis confocal (DAC) microscope that is capable of in vivo fluorescence imaging of skin, using both mouse models and human skin. Individual keratinocytes in the epidermis were observed in three-dimensional image stacks after topical administration of near-infrared (NIR) dyes as contrast agents. This suggested that the DAC microscope may have utility in assessing the clinical effects of a small interfering RNA (siRNA)-based therapeutic (TD101) that targets the causative mutation in pachyonychia congenita (PC) patients. The data indicated that (1) formulated indocyanine green (ICG) readily penetrated hyperkeratotic PC skin and normal callused regions compared with nonaffected areas, and (2) TD101-treated PC skin revealed changes in tissue morphology, consistent with reversion to nonaffected skin compared with vehicle-treated skin. In addition, siRNA was conjugated to NIR dye and shown to penetrate through the stratum corneum barrier when topically applied to mouse skin. These results suggest that in vivo confocal microscopy may provide an informative clinical end point to evaluate the efficacy of experimental molecular therapeutics. PMID:21191407

  11. Mechanisms of pruritogen-induced activation of itch nerves in isolated mouse skin.

    PubMed

    Ru, F; Sun, H; Jurcakova, D; Herbstsomer, R A; Meixong, J; Dong, X; Undem, B J

    2017-02-19

    Chloroquine (CQ) and histamine are pruritogens commonly used to study itch in the mouse. A novel skin-nerve preparation was used to evaluate chloroquine (CQ)- and histamine- induced activation of afferent nerves in the dorsal thoracic skin of the mouse. All CQ sensitive nerves were C-fibres, and were also sensitive to histamine. The response to CQ, but not histamine, was largely absent in mrgpr cluster Δ -/- mice supporting the hypothesis that CQ evokes itch largely via stimulation of MrgprA3 receptors. The CQ-induced action potential discharge was largely absent in phospholipase Cβ3 knockout animals. The CQ and histamine responses were not influenced by removal of TRPA1, TRPV1, TRPC3 or TRPC6, nor by the TRP channel blocker Ruthenium Red. The bouts of scratching in response to CQ was not different between wild type and TRPA1 deficient mice. A selective inhibitor of TMEM16A, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic acid (MONNA) inhibited CQ-induced action potential discharge at itch nerve terminals and bouts of scratching by about 50%. Although TRPA1 and TRPV1 channels may be involved in the scratching responses to intradermal pruitogens, this is unlikely due to an effect at the nerve terminals, where chloride channels may play a more important role. This article is protected by copyright. All rights reserved.

  12. A transgenic mouse for imaging caspase-dependent apoptosis within the skin.

    PubMed

    Khanna, Divya; Hamilton, Christin A; Bhojani, Mahaveer S; Lee, Kuei C; Dlugosz, Andrej; Ross, Brian D; Rehemtulla, Alnawaz

    2010-07-01

    Apoptosis is an essential process for the maintenance of normal physiology. The ability to noninvasively image apoptosis in living animals would provide unique insights into its role in normal and disease processes. Herein, a recombinant reporter consisting of beta-galactosidase gene flanked by two estrogen receptor regulatory domains and intervening Asp-Glu-Val-Glu sequences was constructed to serve as a tool for in vivo assessment of apoptotic activity. The results demonstrate that when expressed in its intact form, the hybrid reporter had undetectable beta-galactosidase activity. Caspase 3 activation in response to an apoptotic stimulus resulted in cleavage of the reporter, and thereby reconstitution of beta-galactosidase activity. Enzymatic activation of the reporter during an apoptotic event enabled noninvasive measurement of beta-galactosidase activity in living cells, which correlated with traditional measures of apoptosis in a dose- and time-dependent manner. Using a near-infrared fluorescent substrate of beta-galactosidase (9H-{1,3-dichloro-9,9-dimethylacridin-2-one-7-yl} beta-D-galactopyranoside), noninvasive in vivo imaging of apoptosis was achieved in a xenograft tumor model in response to proapoptotic therapy. Finally, a transgenic mouse model was developed expressing the ER-LACZ-ER reporter within the skin. This reporter and transgenic mouse could serve as a unique tool for the study of apoptosis in living cells and animals, especially in the context of skin biology.

  13. Collagen metabolism in ultraviolet irradiated hairless mouse skin and its correlation to histochemical observations.

    PubMed

    Kligman, L H; Gebre, M; Alper, R; Kefalides, N A

    1989-08-01

    Early biochemical studies of ultraviolet (UV) irradiated human skin reported a loss of insoluble collagen with a concomitant increase in the soluble fraction. Recent work has described an early increase in type III collagen during chronic irradiation of hairless mice as determined by cyanogen bromide digests of whole skin. In order to understand the correlation of these events and those seen with histochemistry, in the present study we irradiated hairless mice for up to 24 weeks with approximately 4 minimal erythema doses (MEDs) of UVB thrice weekly with Westinghouse FS-40 bulbs. Skin samples were taken at 4-week intervals from irradiated and age-matched control mice. Collagen was isolated from other skin proteins by acid extraction, pepsin digestion, and salt precipitation. Estimates of types I and III collagen were made by interrupted polyacrylamide gel electrophoresis and densitometric scanning. Compared with unirradiated controls, there was a small increase in the ratio of type III to total collagen after 8 weeks of UV. There were no significant increases at later time points until after 24 weeks of radiation. Total collagen in normal mouse skin, determined by hydroxyproline content, remained constant over the 24 weeks, while UV radiation produced significant increases at 4, 8, 12, and 16 weeks, returning to control levels at week 20. There was no change in the degree of hydroxylation at any time point in either group. Thus, chronic UV exposure resulted in increased collagen synthesis until late in the course of irradiation. Because there is a lack of consistent change in the ratio of type III to total collagen, the early increases in collagen content may represent both types I and III, synthesized in relatively unchanging proportions.

  14. Cellular events during scar-free skin regeneration in the spiny mouse, Acomys.

    PubMed

    Brant, Jason O; Yoon, Jung H; Polvadore, Trey; Barbazuk, William Brad; Maden, Malcolm

    2016-01-01

    In contrast to the lab mouse, Mus musculus, several species of spiny mouse, Acomys, can regenerate epidermis, dermis, hairs, sebaceous glands with smooth muscle erector pili muscles and skeletal muscle of the panniculus carnonsus after full thickness skin wounding. Here, we have compared the responses of these scarring and nonscarring organisms concentrating on the immune cells and wound cytokines, cell proliferation, and the collagenous components of the wound bed and scar. The blood of Acomys is very neutropenic but there are greater numbers of mast cells in the Acomys wound than the Mus wound. Most importantly there are no F4/80 macrophages in the Acomys wound and many proinflammatory cytokines are either absent or in very low levels which we suggest may be primarily responsible for the excellent regenerative properties of the skin of this species. There is little difference in cell proliferation in the two species either in the epidermis or mesenchymal tissues but the cell density and matrix composition of the wound is very different. In Mus there are 8 collagens which are up-regulated at least 5-fold in the wound creating a strongly trichrome-positive matrix whereas in Acomys there are very few collagens present and the matrix shows only light trichrome staining. The major component of the Mus matrix is collagen XII which is up-regulated between 10 and 30-fold after wounding. These results suggest that in the Acomys wound the absence of many cytokines resulting in the lack of macrophages is responsible for the failure to up-regulate fibrotic collagens, a situation which permits a regenerative response within the skin rather than the generation of a scar.

  15. Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes.

    PubMed

    Muryoi, T; Kasturi, K N; Kafina, M J; Cram, D S; Harrison, L C; Sasaki, T; Bona, C A

    1992-04-01

    We have generated for the first time monoclonal antibodies (mAbs) specific for topoisomerase I (topo I) from scleroderma patients, and tight skin mice which develop a scleroderma-like syndrome. The epitope specificity of these antibodies has been determined using a series of fusion proteins containing contiguous portions of topo I polypeptide. Western blot analysis demonstrated that both human and mouse mAbs bound strongly to fusion protein C encompassing the NH2-terminal portion of the enzyme, and weakly to fusion proteins F and G containing regions close to the COOH-terminal end of the molecule. This crossreactivity is related to a tripeptide sequence homology in F, G, and C fusion proteins. It is interesting that a pentapeptide sequence homologous to that in fusion protein C was identified in the UL70 protein of cytomegalovirus, suggesting that activation of autoreactive B cell clones by molecular mimicry is possible. Both human and mouse mAbs exhibiting the same antigen specificity, also share an interspecies cross-reactive idiotope. These data suggest that B cell clones producing antitopo autoantibodies present in human and mouse repertoire are conserved during phylogeny, and are activated during the development of scleroderma disease.

  16. Antitopoisomerase I monoclonal autoantibodies from scleroderma patients and tight skin mouse interact with similar epitopes

    PubMed Central

    1992-01-01

    We have generated for the first time monoclonal antibodies (mAbs) specific for topoisomerase I (topo I) from scleroderma patients, and tight skin mice which develop a scleroderma-like syndrome. The epitope specificity of these antibodies has been determined using a series of fusion proteins containing contiguous portions of topo I polypeptide. Western blot analysis demonstrated that both human and mouse mAbs bound strongly to fusion protein C encompassing the NH2-terminal portion of the enzyme, and weakly to fusion proteins F and G containing regions close to the COOH-terminal end of the molecule. This crossreactivity is related to a tripeptide sequence homology in F, G, and C fusion proteins. It is interesting that a pentapeptide sequence homologous to that in fusion protein C was identified in the UL70 protein of cytomegalovirus, suggesting that activation of autoreactive B cell clones by molecular mimicry is possible. Both human and mouse mAbs exhibiting the same antigen specificity, also share an interspecies cross-reactive idiotope. These data suggest that B cell clones producing antitopo autoantibodies present in human and mouse repertoire are conserved during phylogeny, and are activated during the development of scleroderma disease. PMID:1372644

  17. Schistosoma japonicum migration through mouse skin compared histologically and immunologically with S. mansoni.

    PubMed

    Wang, Lin; Li, Yong-Long; Fishelson, Zvi; Kusel, John R; Ruppel, Andreas

    2005-02-01

    The migration of Schistosoma japonicum and S. mansoni through mouse skin epidermis and dermis was compared by immunofluorescence techniques from 4 to 22 h after infection. At all times, the percentage of parasites detected in the dermis was significantly higher for S. japonicum than for S. mansoni. Thus, S. japonicum migrates more rapidly very early after infection. This agrees with the quicker migration observed previously by this species for later times. Both species expressed antigens related to the cercarial glycocalyx on the parasite body and antigenically detectable elastase in the acetabular glands, at least until 22 h after infection. Bot sets of antigens were also left as "traces" in cercarial migration channels in the skin as well as in skin tissue in the absence of detectable worms or migration channels. The data further substantiate differences between schistosome species in the speed of migration, and suggest that glycocalyx-related antigens and cercarial elastase continue to be expressed for at least 1 day after infection.

  18. Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin.

    PubMed

    Squillante, E; Needham, T; Maniar, A; Kislalioglu, S; Zia, H

    1998-11-01

    The in vitro percutaneous fluxes of propylene glycol (PG), cis-oleic acid (OA) and dimethyl isosorbide (DI) were determined and their effect on nifedipine (N) flux and lag time evaluated. PG, OA and DI flux through hairless mouse (HM) skin was measured in vitro by beta-scintigraphy and N permeation was measured by HPLC under finite and infinite dose conditions. Evaluation of each of the solvents separately showed that pure DI possessed the inherent ability to traverse the skin (12% in 24 h). For the tested formulation after 24 h, 57% of the PG and 40% of the DI had permeated across the skin with nearly linear permeation between 4 and 18 h and the relative order of permeation was PG > DI > N. DI permeation was further aided in the presence of PG and OA. N flux was dependent on concomitant solvent permeation. Over a 24-h test period a dose dependent response was observed for N, with 4.9-15.6 mg of N delivered from the lowest and highest doses, respectively, and the highest dose yielding zero-order flux of 146 (g/h per cm2).

  19. Biological and metabolic response in STS-135 space-flown mouse skin.

    PubMed

    Mao, X W; Pecaut, M J; Stodieck, L S; Ferguson, V L; Bateman, T A; Bouxsein, M L; Gridley, D S

    2014-08-01

    There is evidence that space flight condition-induced biological damage is associated with increased oxidative stress and extracellular matrix (ECM) remodeling. To explore possible mechanisms, changes in gene expression profiles implicated in oxidative stress and in ECM remodeling in mouse skin were examined after space flight. The metabolic effects of space flight in skin tissues were also characterized. Space Shuttle Atlantis (STS-135) was launched at the Kennedy Space Center on a 13-day mission. Female C57BL/6 mice were flown in the STS-135 using animal enclosure modules (AEMs). Within 3-5 h after landing, the mice were euthanized and skin samples were harvested for gene array analysis and metabolic biochemical assays. Many genes responsible for regulating production and metabolism of reactive oxygen species (ROS) were significantly (p < 0.05) altered in the flight group, with fold changes >1.5 compared to AEM control. For ECM profile, several genes encoding matrix and metalloproteinases involved in ECM remodeling were significantly up-/down-regulated following space flight. To characterize the metabolic effects of space flight, global biochemical profiles were evaluated. Of 332 named biochemicals, 19 differed significantly (p < 0.05) between space flight skin samples and AEM ground controls, with 12 up-regulated and 7 down-regulated including altered amino acid, carbohydrate metabolism, cell signaling, and transmethylation pathways. Collectively, the data demonstrated that space flight condition leads to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling. This indicates that astronauts may be at increased risk for pathophysiologic damage or carcinogenesis in cutaneous tissue.

  20. Compressive Viscoelasticity of Freshly Excised Mouse Skin Is Dependent on Specimen Thickness, Strain Level and Rate

    PubMed Central

    Wang, Yuxiang; Marshall, Kara L.; Baba, Yoshichika; Lumpkin, Ellen A.; Gerling, Gregory J.

    2015-01-01

    Although the skin’s mechanical properties are well characterized in tension, little work has been done in compression. Here, the viscoelastic properties of a population of mouse skin specimens (139 samples from 36 mice, aged 5 to 34 weeks) were characterized upon varying specimen thickness, as well as strain level and rate. Over the population, we observed the skin’s viscoelasticity to be quite variable, yet found systematic correlation of residual stress ratio with skin thickness and strain, and of relaxation time constants with strain rates. In particular, as specimen thickness ranged from 211 to 671 μm, we observed significant variation in both quasi-linear viscoelasticity (QLV) parameters, the relaxation time constant (τ1 = 0.19 ± 0.10 s) and steady-state residual stress ratio (G∞ = 0.28 ± 0.13). Moreover, when τ1 was decoupled and fixed, we observed that G∞ positively correlated with skin thickness. Second, as steady-state stretch was increased (λ∞ from 0.22 to 0.81), we observed significant variation in both QLV parameters (τ1 = 0.26 ± 0.14 s, G∞ = 0.47 ± 0.17), and when τ1 was fixed, G∞ positively correlated with stretch level. Third, as strain rate was increased from 0.06 to 22.88 s−1, the median time constant τ1 varied from 1.90 to 0.31 s, and thereby negatively correlated with strain rate. These findings indicate that the natural range of specimen thickness, as well as experimental controls of compression level and rate, significantly influence measurements of skin viscoelasticity. PMID:25803703

  1. Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential.

    PubMed

    Hanausek, Margaret; Walaszek, Zbigniew; Viaje, Aurora; LaBate, Michael; Spears, Erick; Farrell, David; Henrich, Richard; Tveit, Ann; Walborg, Earl F; Slaga, Thomas J

    2004-03-01

    Screening of newly synthesized organic peroxides for tumor initiating/promoting activity would be greatly facilitated if predictive methodologies could be developed using topical exposures shorter than those required for definitive tumor assessment in mouse skin models. Nine organic peroxides [benzoyl peroxide (BZP), di-t-butyl peroxide (DTBP), t-butyl peroxybenzoate (TBPB), p-t-butyl isopropylbenzene hydroperoxide (TBIBHP), cumene hydroperoxide (CHP), dicetyl peroxydicarbonate (DPD), dicumyl peroxide (DCP), methyl ethyl ketone peroxide (MEKP) and O,O-t-butyl-O-(2-ethylhexyl) monoperoxycarbonate (TBEC)] were evaluated for their ability to increase biomarkers of tumor promotion in mouse skin, i.e. sustained epidermal hyperplasia, dermal inflammation and oxidative DNA damage. Evaluations were performed using SENCAR mice exposed topically for 4 weeks. The organic peroxides varied in their effects on these biomarkers. BZP, TBPB and TBIBHP exhibited significant increases in all three biomarkers associated with tumor promoting activity, CHP produced increases only in sustained epidermal hyperplasia and dermal inflammation, MEKP and DCP produced increases only in sustained epidermal hyperplasia and TBEC produced an increase only in dermal inflammation. DTBP and DPD had no effect on the three parameters studied. TBPB and TBIBHP were selected for further examination of their ability to produce mutations in codons 12, 13 and 61 of the c-Ha-ras protooncogene, i.e. those mutations known to be involved in the initiation of mouse skin tumors, because they were the only peroxides to exhibit significant positive results in all assays except the Ha-ras mutation following 4 weeks of exposure. Evaluations were performed using SENCAR mice dosed topically for 8 or 12 weeks in a complete carcinogenesis protocol or 16 weeks in an initiation/promotion protocol using 7,12-dimethylbenz[a]anthracene, urethane, benzo[a]pyrene and N-methyl-N'-nitro-N-nitrosoguanidine as positive controls

  2. The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin

    PubMed Central

    Chakravarti, Dhrubajyoti; Venugopal, Divya; Mailander, Paula C.; Meza, Jane L.; Higginbotham, Sheila; Cavalieri, Ercole L.; Rogan, Eleanor G.

    2008-01-01

    Polycyclic aromatic hydrocarbons (PAH) form stable and depurinating DNA adducts in mouse skin to induce preneoplastic mutations. Some mutations transform cells, which then clonally expand to establish tumors. Strong clues about the mutagenic mechanism can be obtained if the PAH-DNA adducts can be correlated with both preneoplastic and tumor mutations. To this end, we studied mutagenesis in PAH-treated early preneoplastic skin (1 day after exposure) and in the induced papillomas in SENCAR mice. Papillomas were studied by PCR amplification of the H-ras gene and sequencing. For benzo[a]pyrene (BP), BP-7,8-dihydrodiol (BPDHD), 7,12-dimethylbenz[a]anthracene (DMBA) and dibenzo[a,l]pyrene (DB[a,l]P), the codon 13 (GGC to GTC) and codon 61 (CAA to CTA) mutations in papillomas corresponded to the relative levels of Gua and Ade-depurinating adducts, despite BP and BPDHD forming significant amounts of stable DNA adducts. Such a relationship was expected for DMBA and DB[a,l]P, as they formed primarily depurinating adducts. These results suggest that depurinating adducts play a major role in forming the tumorigenic mutations. To validate this correlation, preneoplastic skin mutations were studied by cloning H-ras PCR products and sequencing individual clones. DMBA- and DB[a,l]P-treated skin showed primarily A.T to G.C mutations, which correlated with the high ratio of the Ade/Gua-depurinating adducts. Incubation of skin DNA with T.G-DNA glycosylase eliminated most of these A.T to G.C mutations, indicating that they existed as G.T heteroduplexes, as would be expected if they were formed by errors in the repair of abasic sites generated by the depurinating adducts. BP and its metabolites induced mainly G.C to T.A mutations in preneoplastic skin. However, PCR over unrepaired anti-BPDE-N2dG adducts can generate similar mutations as artifacts of the study protocol, making it difficult to establish an adduct-mutation correlation for determining which BP-DNA adducts induce the early

  3. Simultaneous dual modality optical and MR imaging of mouse dorsal skin-fold window chamber

    NASA Astrophysics Data System (ADS)

    Salek, Mir Farrokh; Pagel, Mark D.; Gmitro, Arthur F.

    2011-02-01

    Optical imaging and MRI have both been used extensively to study tumor microenvironment. The two imaging modalities are complementary and can be used to cross-validate one another for specific measurements. We have developed a modular platform that is capable of doing optical microscopy inside an MRI instrument. To do this, an optical relay system transfers the image to outside of the MR bore to a commercial grade CCD camera. This enables simultaneous optical and MR imaging of the same tissue and thus creates the ideal situation for comparative or complementary studies using both modalities. Initial experiments have been done using GFP labeled prostate cancer cells implanted in mouse dorsal skin fold window chamber. Vascular hemodynamics and vascular permeability were studied using our imaging system. Towards this goal, we developed a dual MR-Optical contrast agent by labeling BSA with both Gd-DTPA and Alexa Fluor. Overall system design and results of these preliminary vascular studies are presented.

  4. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis

    PubMed Central

    Aragona, Mariaceleste; Dekoninck, Sophie; Rulands, Steffen; Lenglez, Sandrine; Mascré, Guilhem; Simons, Benjamin D.; Blanpain, Cédric

    2017-01-01

    Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. Here, we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. Using a combination of proliferation kinetics experiments and molecular profiling, we identify the gene signatures associated with proliferation, differentiation and migration in different regions surrounding the wound. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. Lineage tracing and quantitative clonal analysis reveal that, following wounding, progenitors divide more rapidly, but conserve their homoeostatic mode of division, leading to their rapid depletion, whereas SCs become active, giving rise to new progenitors that expand and repair the wound. These results have important implications for tissue regeneration, acute and chronic wound disorders. PMID:28248284

  5. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

    SciTech Connect

    Abel, E.L.; Boulware, S.; Fields, T.; McIvor, E.; Powell, K.L.; DiGiovanni, J.; Vasquez, K.M.; MacLeod, M.C.

    2013-02-01

    Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas. -- Highlights: ► Sulforaphane induces increased levels of glutathione in mouse skin. ► Sulforaphane induces increased levels of GSTA4 in mouse skin. ► Sulforaphane, applied after CEES-treatment, completely abolishes CEES-mutagenesis. ► The therapeutic effect may suggest a long biological half-life for CEES in vivo.

  6. Analyzing the miRNA-Gene Networks to Mine the Important miRNAs under Skin of Human and Mouse

    PubMed Central

    Gong, Husile

    2016-01-01

    Genetic networks provide new mechanistic insights into the diversity of species morphology. In this study, we have integrated the MGI, GEO, and miRNA database to analyze the genetic regulatory networks under morphology difference of integument of humans and mice. We found that the gene expression network in the skin is highly divergent between human and mouse. The GO term of secretion was highly enriched, and this category was specific in human compared to mouse. These secretion genes might be involved in eccrine system evolution in human. In addition, total 62,637 miRNA binding target sites were predicted in human integument genes (IGs), while 26,280 miRNA binding target sites were predicted in mouse IGs. The interactions between miRNAs and IGs in human are more complex than those in mouse. Furthermore, hsa-miR-548, mmu-miR-466, and mmu-miR-467 have an enormous number of targets on IGs, which both have the role of inhibition of host immunity response. The pattern of distribution on the chromosome of these three miRNAs families is very different. The interaction of miRNA/IGs has added the new dimension in traditional gene regulation networks of skin. Our results are generating new insights into the gene networks basis of skin difference between human and mouse. PMID:27689084

  7. Development of a bioengineered skin-humanized mouse model for psoriasis: dissecting epidermal-lymphocyte interacting pathways.

    PubMed

    Guerrero-Aspizua, Sara; García, Marta; Murillas, Rodolfo; Retamosa, Luisa; Illera, Nuria; Duarte, Blanca; Holguín, Almudena; Puig, Susana; Hernández, Maria Isabel; Meana, Alvaro; Jorcano, Jose Luis; Larcher, Fernando; Carretero, Marta; Del Río, Marcela

    2010-12-01

    Over the past few years, whole skin xenotransplantation models that mimic different aspects of psoriasis have become available. However, these models are strongly constrained by the lack of skin donor availability and homogeneity. We present in this study a bioengineering-based skin-humanized mouse model for psoriasis, either in an autologous version using samples derived from psoriatic patients or, more importantly, in an allogeneic context, starting from skin biopsies and blood samples from unrelated healthy donors. After engraftment, the regenerated human skin presents the typical architecture of normal human skin but, in both cases, immunological reconstitution through intradermal injection in the regenerated skin using in vitro-differentiated T1 subpopulations as well as recombinant IL-17 and IL-22 Th17 cytokines, together with removal of the stratum corneum barrier by a mild abrasive treatment, leads to the rapid conversion of the skin into a bona fide psoriatic phenotype. Major hallmarks of psoriasis were confirmed by the evaluation of specific epidermal differentiation and proliferation markers as well as the mesenchymal milieu, including angiogenesis and infiltrate. Our bioengineered skin-based system represents a robust platform to reliably assess the molecular and cellular mechanisms underlying the complex interdependence between epidermal cells and the immune system. The system may also prove suitable to assess preclinical studies that test the efficacy of novel therapeutic treatments and to predict individual patient response to therapy.

  8. Epidermal hyperplasia in mouse skin following treatment with alternative drinking water disinfectants

    SciTech Connect

    Robinson, M.; Bull, R.J.; Schamer, M.; Long, R.E.

    1986-11-01

    Female SENCAR mice were treated with aqueous solutions of hypochlorous acid (HOCl), sodium hypochlorite (NaOCl), chlorine dioxide (ClO/sub 2/), and monochloramine (NH/sub 2/Cl) by whole body exposure (except head) for a 10-min period for 4 days in the first experiment and for 1 day (except NH/sub 2/Cl) in the second experiment. Animals were sacrificed the day following the last treatment (experiment 1) or on day 1, 2, 3, 4, 5, 8, 10, and 12 following treatment (experiment 2), and skin thickness was measured by light microscopy. Concentrations of disinfectants were 1, 10, 100, 300, and 1000 mg/L, for experiment 1 and 1000 mg/L for experiment 2. Thickness of the interfollicular epidermis (IFE) for control animals was 15.4 +/- 1.5 ..mu..m. After 4 days of treatment at 1000 mg/L, HOCl and ClO/sub 2/ increased thickness to 30 +/- 7.0 and 40.2 +/- 11.8, and NaOCl increased thickness to 25.2 +/- 6.1 ..mu.. m. The response to HOCl was found to be dose-related. The time-course study following a single treatment of 1000 mg/L HOCl, showed a progression of IFE thickening of from 18.3 +/- 1.4 at 1 day to 30.8 +/- 8.0 at 8 days, decreasing to 19.1 +/- 6.2 ..mu..m at 12 days. ClO/sub 2/ and NaOCl when tested in this manner did not produce increased thickness of IFE with time, but rather gave a persistent level of increase that remained for the 12 days. NH/sub 2/Cl reduced skin thickness to 13.6 +/- 6.1 ..mu..m. Examination of sections of skin treated with HOCl and ClO/sub 2/ indicated an increase in cell numbers. HOCl and ClO/sub 2/ are therefore capable of inducting hyperplastic responses in the mouse skin. The basis for the decrease in skin thickness resulting from NH/sub 2/Cl treatment remains to be established.

  9. Establishment of a cell line with features of early dendritic cell precursors from fetal mouse skin.

    PubMed

    Girolomoni, G; Lutz, M B; Pastore, S; Assmann, C U; Cavani, A; Ricciardi-Castagnoli, P

    1995-08-01

    During ontogeny, the skin is progressively populated by major histocompatibility complex class II-negative dendritic cell (DC) precursors that then mature into efficient antigen-presenting cells (APC). To characterize these DC progenitors better, we generated myeloid cell lines from fetal mouse skin by infecting cell suspensions with a retroviral vector carrying an envAKR-mycMH2 fusion gene. These cells, represented by the line FSDC, displayed a dendritic morphology and their proliferation in serum-free medium was promoted by granulocyte/macrophage colony-stimulating factor (GM-CSF), but not macrophage-CSF. FSDC expressed strong surface-membrane ATP/ADPase activity, intracellular staining for 2A1 antigen, and a surface phenotype consistent with a myeloid precursor: H-2d,b+, I-Ad,b+, CD54+, CD11b+, CD11c+, 2.4G2+, F4/80+, CD44+, 2F8+, ER-MP 12-, Sca-1+, Sca-2+, NLDC-145-, B7.2+, B7.1-, J11d-, B220-, Thy-1-, and CD3-. FSDC stimulated poorly allogeneic or syngeneic T cells in the primary mixed-leukocyte reaction, and markedly increased this function after treatment with GM-CSF, GM-CSF and interleukin (IL)-4 or interferon-gamma (IFN-gamma); in contrast, stem cell factor, IL-1 alpha and tumor necrosis factor-alpha had no effect. Preculture with IFN-gamma was required for presentation of haptens to primed T cells in vitro. However, FSDC, even after cytokine activation, were less potent APC than adult epidermal Langerhans cells in both of the above assays. Finally, FSDC derivatized with haptens and injected either intravenously or subcutaneously could efficiently induce contact sensitivity responses in naive syngeneic mice. The results indicate that fetal mouse skin is colonized by myeloid precursors possessing a macrophage/immature DC-like surface phenotype and priming capacity in vivo. These cells need further differentiation and activation signals (e.g. cytokines) to express their antigen presenting potential in vitro.

  10. Impairment of skin barrier function via cholinergic signal transduction in a dextran sulphate sodium-induced colitis mouse model.

    PubMed

    Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

    2015-10-01

    Dry skin has been clinically associated with visceral diseases, including liver disease, as well as for our previously reported small intestinal injury mouse model, which have abnormalities in skin barrier function. To clarify this disease-induced skin disruption, we used a dextran sulphate sodium (DSS)-induced colitis mouse model. Following treatment with DSS, damage to the colon and skin was monitored using histological and protein analysis methods as well as the detection of inflammatory mediators in the plasma. Notably, transepidermal water loss was higher, and skin hydration was lower in DSS-treated mice compared to controls. Tumor necrosis factor-alpha (TNF-α), interleukin 6 and NO2-/NO3- levels were also upregulated in the plasma, and a decrease in body weight and colon length was observed in DSS-treated mice. However, when administered TNF-α antibody or an iNOS inhibitor, no change in skin condition was observed, indicating that another signalling mechanism is utilized. Interestingly, the number of tryptase-expressing mast cells, known for their role in immune function via cholinergic signal transduction, was elevated. To evaluate the function of cholinergic signalling in this context, atropine (a muscarinic cholinoceptor antagonist) or hexamethonium (a nicotinic cholinergic ganglion-blocking agent) was administered to DSS-treated mice. Our data indicate that muscarinic acetylcholine receptors (mAChRs) are the primary receptors functioning in colon-to-skin signal transduction, as DSS-induced skin disruption was suppressed by atropine. Thus, skin disruption is likely associated with DSS-induced colitis, and the activation of mast cells via mAChRs is critical to this association.

  11. In Vivo Assessment of Acute UVB Responses in Normal and Xeroderma Pigmentosum (XP-C) Skin-Humanized Mouse Models

    PubMed Central

    García, Marta; Llames, Sara; García, Eva; Meana, Alvaro; Cuadrado, Natividad; Recasens, Mar; Puig, Susana; Nagore, Eduardo; Illera, Nuria; Jorcano, José Luis; Del Rio, Marcela; Larcher, Fernando

    2010-01-01

    In vivo studies of UVB effects on human skin are precluded by ethical and technical arguments on volunteers and inconceivable in cancer-prone patients such as those affected with Xeroderma Pigmentosum (XP). Establishing reliable models to address mechanistic and therapeutic matters thus remains a challenge. Here we have used the skin-humanized mouse system that circumvents most current model constraints. We assessed the UVB radiation effects including the sequential changes after acute exposure with respect to timing, dosage, and the relationship between dose and degree-sort of epidermal alteration. On Caucasian-derived regenerated skins, UVB irradiation (800 J/m2) induced DNA damage (cyclobutane pyrimidine dimers) and p53 expression in exposed keratinocytes. Epidermal disorganization was observed at higher doses. In contrast, in African descent–derived regenerated skins, physiological hyperpigmentation prevented tissue alterations and DNA photolesions. The acute UVB effects seen in Caucasian-derived engrafted skins were also blocked by a physical sunscreen, demonstrating the suitability of the system for photoprotection studies. We also report the establishment of a photosensitive model through the transplantation of XP-C patient cells as part of a bioengineered skin. The inability of XP-C engrafted skin to remove DNA damaged cells was confirmed in vivo. Both the normal and XP-C versions of the skin-humanized mice proved proficient models to assess UVB-mediated DNA repair responses and provide a strong platform to test novel therapeutic strategies. PMID:20558577

  12. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo

    SciTech Connect

    Kundu, Joydeb Kumar; Liu, Lijia; Shin, Jun-Wan; Surh, Young-Joon

    2013-09-06

    Highlights: •Thymoquinone inhibits phorbol ester-induced COX-2 expression in mouse skin. •Thymoquinone attenuates phosphorylation of IκBα and DNA binding of NF-κB in mouse skin. •Thymoquinone inhibits phosphorylation of p38 MAP kinase, JNK and Akt in mouse skin. •Thymoquinone induces the expression of cytoprotective proteins in mouse skin. -- Abstract: Thymoquinone (TQ), the active ingredient of Nigella sativa, has been reported to possess anti-inflammatory and chemopreventive properties. The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory and antioxidative activities of thymoquinone in mouse skin. Pretreatment of female HR-1 hairless mouse skin with TQ attenuated 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). TQ diminished nuclear translocation and the DNA binding of nuclear factor-kappaB (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Pretreatment with TQ attenuated the phosphorylation of Akt, c-Jun-N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-1/2. Moreover, topical application of TQ induced the expression of heme oxygenase-1, NAD(P)H-quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin. Taken together, the inhibitory effects of TQ on TPA-induced COX-2 expression and NF-κB activation, and its ability to induce the expression of cytoprotective proteins provide a mechanistic basis of anti-inflammatory and antioxidative effects of TQ in hairless mouse skin.

  13. Topical glycerol monooleate/propylene glycol formulations enhance 5-aminolevulinic acid in vitro skin delivery and in vivo protophorphyrin IX accumulation in hairless mouse skin.

    PubMed

    Steluti, Regilene; De Rosa, Fernanda Scarmato; Collett, John; Tedesco, Antônio Cláudio; Bentley, Maria Vitória Lopes Badra

    2005-08-01

    Photodynamic therapy (PDT), a potential therapy for cancer treatment, utilizes exogenously applied or endogenously formed photosensitizers, further activated by light in an appropriate wavelength and dose to induce cell death through free radical formation. 5-Aminolevulinic acid (5-ALA) is a pro-drug which can be converted to the effective photosensitizer, protoporphyrin IX (PpIX). However, the use of 5-ALA in PDT is limited by the low penetration capacity of this highly hydrophilic molecule into appropriate skin layers. In the present study, we propose to increase 5-ALA penetration by using formulations containing glycerol monooleate (GMO), an interesting and useful component of pharmaceutical formulations. Propylene glycol solutions containing different concentrations of GMO significantly increased the in vitro skin permeation/retention of 5-ALA in comparison to control solutions. In vivo studies also showed increased PpIX accumulation in mouse hairless skin, after the use of topical 5-ALA formulations containing GMO in a concentration-dependent manner. The results show that skin 5-ALA penetration and PpIX accumulation, important factors for the success of topical 5-ALA-PDT in skin cancer, are optimized by GMO/propylene glycol formulations.

  14. Multimodality pH imaging in a mouse dorsal skin fold window chamber model

    NASA Astrophysics Data System (ADS)

    Leung, Hui Min; Schafer, Rachel; Pagel, Mark M.; Robey, Ian F.; Gmitro, Arthur F.

    2013-03-01

    Upregulate levels of expression and activity of membrane H+ ion pumps in cancer cells drives the extracellular pH (pHe,) to values lower than normal. Furthermore, disregulated pH is indicative of the changes in glycolytic metabolism in tumor cells and has been shown to facilitate extracellular tissue remodeling during metastasis Therefore, measurement of pHe could be a useful cancer biomarker for diagnostic and therapy monitoring evaluation. Multimodality in-vivo imaging of pHe in tumorous tissue in a mouse dorsal skin fold window chamber (DSFWC) model is described. A custom-made plastic window chamber structure was developed that is compatible with both imaging optical and MR imaging modalities and provides a model system for continuous study of the same tissue microenvironment on multiple imaging platforms over a 3-week period. For optical imaging of pHe, SNARF-1 carboxylic acid is injected intravenously into a SCID mouse with an implanted tumor. A ratiometric measurement of the fluorescence signal captured on a confocal microscope reveals the pHe of the tissue visible within the window chamber. This imaging method was used in a preliminary study to evaluate sodium bicarbonate as a potential drug treatment to reverse tissue acidosis. For MR imaging of pHe the chemical exchange saturation transfer (CEST) was used as an alternative way of measuring pHe in a DSFWC model. ULTRAVIST®, a FDA approved x-ray/CT contrast agent has been shown to have a CEST effect that is pH dependent. A ratiometric analysis of water saturation at 5.6 and 4.2 ppm chemical shift provides a means to estimate the local pHe.

  15. An Optimized Method for Extracting Bacterial RNA from Mouse Skin Tissue Colonized by Mycobacterium ulcerans.

    PubMed

    Robbe-Saule, Marie; Babonneau, Jérémie; Sismeiro, Odile; Marsollier, Laurent; Marion, Estelle

    2017-01-01

    Bacterial transcriptome analyses during host colonization are essential to decipher the complexity of the relationship between the bacterium and its host. RNA sequencing (RNA-seq) is a promising approach providing valuable information about bacterial adaptation, the host response and, in some cases, mutual tolerance underlying crosstalk, as recently observed in the context of Mycobacterium ulcerans infection. Buruli ulcer is caused by M. ulcerans. This neglected disease is the third most common mycobacterial disease worldwide. Without treatment, M. ulcerans provokes massive skin ulcers. A healing process may be observed in 5% of Buruli ulcer patients several months after the initiation of disease. This spontaneous healing process suggests that some hosts can counteract the development of the lesions caused by M. ulcerans. Deciphering the mechanisms involved in this process should open up new treatment possibilities. To this end, we recently developed the first mouse model for studies of the spontaneous healing process. We have shown that the healing process is based on mutual tolerance between the bacterium and its host. In this context, RNA-seq seems to be the most appropriate method for deciphering bacterial adaptation. However, due to the low bacterial load in host tissues, the isolation of mycobacterial RNA from skin tissue for RNA-seq analysis remains challenging. We developed a method for extracting and purifying mycobacterial RNA whilst minimizing the amount of host RNA in the sample. This approach was based on the extraction of bacterial RNA by a differential lysis method. The challenge in the development of this method was the choice of a lysis system favoring the removal of host RNA without damage to the bacterial cells. We made use of the thick, resistant cell wall of M. ulcerans to achieve this end.

  16. An Optimized Method for Extracting Bacterial RNA from Mouse Skin Tissue Colonized by Mycobacterium ulcerans

    PubMed Central

    Robbe-Saule, Marie; Babonneau, Jérémie; Sismeiro, Odile; Marsollier, Laurent; Marion, Estelle

    2017-01-01

    Bacterial transcriptome analyses during host colonization are essential to decipher the complexity of the relationship between the bacterium and its host. RNA sequencing (RNA-seq) is a promising approach providing valuable information about bacterial adaptation, the host response and, in some cases, mutual tolerance underlying crosstalk, as recently observed in the context of Mycobacterium ulcerans infection. Buruli ulcer is caused by M. ulcerans. This neglected disease is the third most common mycobacterial disease worldwide. Without treatment, M. ulcerans provokes massive skin ulcers. A healing process may be observed in 5% of Buruli ulcer patients several months after the initiation of disease. This spontaneous healing process suggests that some hosts can counteract the development of the lesions caused by M. ulcerans. Deciphering the mechanisms involved in this process should open up new treatment possibilities. To this end, we recently developed the first mouse model for studies of the spontaneous healing process. We have shown that the healing process is based on mutual tolerance between the bacterium and its host. In this context, RNA-seq seems to be the most appropriate method for deciphering bacterial adaptation. However, due to the low bacterial load in host tissues, the isolation of mycobacterial RNA from skin tissue for RNA-seq analysis remains challenging. We developed a method for extracting and purifying mycobacterial RNA whilst minimizing the amount of host RNA in the sample. This approach was based on the extraction of bacterial RNA by a differential lysis method. The challenge in the development of this method was the choice of a lysis system favoring the removal of host RNA without damage to the bacterial cells. We made use of the thick, resistant cell wall of M. ulcerans to achieve this end. PMID:28392785

  17. Antiinflammatory and Antiphotodamaging Effects of Ergostatrien-3β-ol, Isolated from Antrodia camphorata, on Hairless Mouse Skin.

    PubMed

    Kuo, Yueh-Hsiung; Lin, Tzu-Yu; You, Ya-Jhen; Wen, Kuo-Ching; Sung, Ping-Jyun; Chiang, Hsiu-Mei

    2016-09-10

    Ergostatrien-3β-ol (EK100), isolated from the submerged whole broth of Antrodia camphorata, has antidiabetic, hyperlipidemic, and hepatoprotective activities. However, the antiphotodamage activity of EK100 has still not been revealed. Inflammation and collagen degradation contribute to skin photodamage and premature aging. In the present study, in vivo experiments were designed to investigate the antiinflammatory and antiphotodamaging activities of EK100 in hairless mice by physiological and histological analysis of the skin. Results indicated that topical application of EK100 (25 and 100 μM) for 10 weeks efficiently inhibited ultraviolet B (UVB)-induced wrinkle formation, erythema, and epidermal thickness in the mice skin. EK100 also restored UVB-induced collagen content reduction in hairless mice skin. In addition, the immunohistochemistry results indicated that EK100 significantly inhibited the UVB-induced expression of matrix metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and nuclear factor kappaB (NF-κB) in the mouse skin. The expression of these proteins was similar to the Normal group after 100 μM EK100 treatment. EK100 inhibited collagen degradation in the skin through MMP-1 inhibition and antiinflammation. EK100 significantly reduced the transepidermal water loss (TEWL), indicating that EK100 protected skin from UVB-induced damage. Our findings strongly suggest that EK100 has significant beneficial antiinflammatory and antiphotoaging activities and that EK100 can be developed as an antiphotodamaging agent.

  18. Formation of DNA adducts in the skin of psoriasis patients, in human skin in organ culture, and in mouse skin and lung following topical application of coal-tar and juniper tar.

    PubMed

    Schoket, B; Horkay, I; Kósa, A; Páldeák, L; Hewer, A; Grover, P L; Phillips, D H

    1990-02-01

    Preparations of coal-tar and juniper tar (cade oil) that are used in the treatment of psoriasis are known to contain numerous potentially carcinogenic polycyclic aromatic hydrocarbons (PAH). Evidence of covalent binding to DNA by components of these mixtures was sought in a) human skin biopsy samples from 12 psoriasis patients receiving therapy with these agents, b) human skin explants maintained in organ culture and treated topically with the tars, and c) the skin and lungs of mice treated with repeated doses of the formulations following the regimen used in the clinic. DNA was isolated from the human and mouse tissues and digested enzymically to mononucleotides. 32P-Post-labeling analysis revealed the presence of aromatic DNA adducts in the biopsy samples at levels of up to 0.4 fmol total adducts/microgram DNA. Treatment of human skin in organ culture produced similar levels of adducts, while treatment with dithranol, a non-mutagenic therapeutic agent, resulted in chromatograms indistinguishable from those from untreated controls. In mouse skin, coal-tar ointment and juniper tar gave similar DNA adduct levels, with a similar time-course of removal: maximum levels (0.5 fmol/microgram DNA) at 24 h after the final treatment declined rapidly to 0.05 fmol/microgram at 7 d, thereafter declining slowly over the succeeding 25 d. However, while coal-tar ointment produced only very low levels of adducts in mouse lung (less than 0.03 fmol/microgram DNA), juniper tar produced adducts at a high level (0.7 fmol/microgram DNA) that were persistent in this tissue. These results provide direct evidence for the formation of potentially carcinogenic DNA damage in human and mouse tissue by components of these therapeutic tar preparations.

  19. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype.

    PubMed

    Ballarò, Costanza; Ceccarelli, Sara; Tiveron, Cecilia; Tatangelo, Laura; Salvatore, Anna Maria; Segatto, Oreste; Alemà, Stefano

    2005-08-01

    Although it has been clearly established that negative feedback loops have a fundamental role in the regulation of epidermal growth factor receptor (EGFR) signalling in flies, their role in the regulation of mammalian EGFR has been inferred only recently from in vitro studies. Here, we report on the forced expression of RALT/MIG-6, a negative feedback regulator of ErbB receptors, in mouse skin. A RALT transgene driven by the K14 promoter generated a dose-dependent phenotype resembling that caused by hypomorphic and antimorphic Egfr alleles-that is, wavy coat, curly whiskers and open eyes at birth. Ex vivo keratinocytes from K14-RALT mice showed reduced biochemical and biological responses when stimulated by ErbB ligands. Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling. Thus, RALT behaves as a suppressor of EGFR signalling in mouse skin.

  20. Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype

    PubMed Central

    Ballarò, Costanza; Ceccarelli, Sara; Tiveron, Cecilia; Tatangelo, Laura; Salvatore, Anna Maria; Segatto, Oreste; Alemà, Stefano

    2005-01-01

    Although it has been clearly established that negative feedback loops have a fundamental role in the regulation of epidermal growth factor receptor (EGFR) signalling in flies, their role in the regulation of mammalian EGFR has been inferred only recently from in vitro studies. Here, we report on the forced expression of RALT/MIG-6, a negative feedback regulator of ErbB receptors, in mouse skin. A RALT transgene driven by the K14 promoter generated a dose-dependent phenotype resembling that caused by hypomorphic and antimorphic Egfr alleles—that is, wavy coat, curly whiskers and open eyes at birth. Ex vivo keratinocytes from K14-RALT mice showed reduced biochemical and biological responses when stimulated by ErbB ligands. Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling. Thus, RALT behaves as a suppressor of EGFR signalling in mouse skin. PMID:16007071

  1. The plasma membrane-associated NADH oxidase (ECTO-NOX) of mouse skin responds to blue light

    NASA Technical Reports Server (NTRS)

    Morre, D. James; Morre, Dorothy M.

    2003-01-01

    NADH oxidases of the external plasma membrane surface (ECTO-NOX proteins) are characterized by oscillations in activity with a regular period length of 24 min. Explants of mouse skin exhibit the oscillatory activity as estimated from the decrease in A(340) suggesting that individual ECTO-NOX molecules must somehow be induced to function synchronously. Transfer of explants of mouse skin from darkness to blue light (495 nm, 2 min, 50 micromol m(-1) s(-1)) resulted in initiation of a new activity maximum (entrainment) with a midpoint 36 min after light exposure followed by maxima every 24 min thereafter. Addition of melatonin resulted in a new maximum 24 min after melatonin addition. The findings suggest that the ECTO-NOX proteins play a central role in the entrainment of the biological clock both by light and by melatonin.

  2. Quantitation of ceramides in nude mouse skin by normal-phase liquid chromatography and atmospheric pressure chemical ionization mass spectrometry.

    PubMed

    Liou, Yi-Bo; Sheu, Ming-Thau; Liu, Der-Zen; Lin, Shan-Yang; Ho, Hsiu-O

    2010-06-01

    A sensitive and accurate normal-phase liquid chromatography and atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS) method for determining the standard ceramide [NS] (Cer[NS]) was developed and validated so as to improve the traditional thin-layer chromatography (TLC) technique and LC-electrospray ionization (ESI)-MS method to profile and quantify ceramides in nude mouse skin. Normal-phase LC-APCI-MS was optimized to separate the nine classes of ceramides presented in the stratum corneum (SC) of nude mouse skin. A normal-phase silica column eluted with the gradient system from heptane:acetone/butanol (90:10, v/v) of 75:25 to 100% acetone/butanol (90:10, v/v) (with each solvent containing 0.1% [v/v] triethylamine and 0.1% [v/v] formic acid) at a flow rate of 0.8 ml/min was found to be optimal for analyzing standard Cer[NS]. The analysis of Cer[NS] was validated and employed as the standard for constructing a calibration curve to quantitate all classes of ceramides. This method was applied to profile the classes and contents of ceramides in the SC of nude mouse skin and proved to be workable. It was concluded that this improved method can be used to directly detect and quantify all classes of ceramides in the SC of nude mouse skin and that it is more convenient and labor-saving than the traditional TLC method.

  3. Moisturizing lotions can increase transdermal absorption of the herbicide 2,4-dichlorophenoxacetic acid across hairless mouse skin.

    PubMed

    Brand, R M; Charron, A R; Sandler, V L; Jendrzejewski, J L

    2007-01-01

    Moisturizing lotions can be an effective treatment for occupationally induced dry skin. These compounds are designed to be hygroscopic and retain water to keep the stratum corneum hydrated, while at the same time enhancing the horny layer to prevent increases in transepidermal water loss (TEWL). Skin hydration levels, however, are known to influence barrier properties. The purpose of this work was to compare skin moisture levels induced by four commercially available moisturizing lotions with their capacity as transdermal penetration enhancers using the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) as a model chemical. Further, the effect of moisturizing the skin after washing with sodium lauryl sulfate (SLS) on transdermal absorption was determined. Skin moisture levels were also measured noninvasively and were correlated to penetration enhancement. Hairless mouse skin was pretreated with commercially available moisturizing lotions either with or without SLS washing and in vitro permeability studies were performed with the herbicide 2,4-D. The data demonstrate that pretreatment with three of the four lotions tested increased the transdermal absorption of 2,4-D as evidenced by cumulative penetration or faster lag times (p < 0.05). Skin moisture levels correlated with the penetration enhancement capabilities of the lotion. Washing the skin with 5% SDS increased the transdermal absorption of 2,4-D (p < 0.05) and application of moisturizing lotions increased the absorption further. In summary moisturizing lotions may influence transdermal penetration of the skin, with the more effective moisturizers having a greater effect on 2,4-D absorption.

  4. Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17

    PubMed Central

    Lee, Mee-Hyun; Lim, Do Young; Kim, Myoung Ok; Lee, Sung-Young; Shin, Seung Ho; Kim, Jae Young; Kim, Sung-Hyun; Kim, Dong Joon; Jung, Sung Keun; Yao, Ke; Kundu, Joydeb Kumar; Lee, Hye Suk; Lee, Cheol-Jung; Dickinson, Sally E.; Alberts, David; Bowden, G.Timothy; Stratton, Steven; Curiel, Clara; Einspahr, Janine; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

    2015-01-01

    Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17. PMID:26271098

  5. Relevance of the mouse skin initiation-promotion model for the classification of carcinogenic substances encountered at the workplace.

    PubMed

    Schwarz, Michael; Thielmann, Heinz W; Meischner, Veronika; Fartasch, Manigé

    2015-06-01

    The Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission of the Deutsche Forschungsgemeinschaft) evaluates chemical substances using scientific criteria to prevent adverse effects on health at the work place. As part of this task there is a need to evaluate tumor promoting activity of chemicals (enhancement of formation of squamous cell carcinomas via premalignant papillomas) obtained from two-stage initiation/promotion experiments using the mouse skin model. In the present communication we address this issue by comparing responses seen in mouse skin with those in humans. We conclude that tumor promotional effects seen in such animal models be carefully analyzed on a case by case basis. Substances that elicit a rather non-specific effect that is restricted to the high dose range are considered to be irrelevant to humans and thus do not require classification as carcinogens. In contrast, substances that might have both a mode of action and a potency similar to the specific effects seen with TPA (12-O-tetradecanoylphorbol-13-acetate), the prototype tumor promoter in mouse skin, which triggers receptor-mediated signal cascades in the very low dose range, have to be classified in a category for carcinogens.

  6. Impact of Cosmetic Lotions on Nanoparticle Penetration through ex vivo C57BL/6 Hairless Mouse and Human Skin: A Comparison Study

    PubMed Central

    Jatana, Samreen; Callahan, Linda M.; Pentland, Alice P.; DeLouise, Lisa A.

    2016-01-01

    Understanding the interactions of nanoparticles (NPs) with skin is important from a consumer and occupational health and safety perspective, as well as for the design of effective NP-based transdermal therapeutics. Despite intense efforts to elucidate the conditions that permit NP penetration, there remains a lack of translatable results from animal models to human skin. The objectives of this study are to investigate the impact of common skin lotions on NP penetration and to quantify penetration differences of quantum dot (QD) NPs between freshly excised human and mouse skin. QDs were mixed in 7 different vehicles, including 5 commercial skin lotions. These were topically applied to skin using two exposure methods; a petri dish protocol and a Franz diffusion cell protocol. QD presence in the skin was quantified using Confocal Laser Scanning Microscopy. Results show that the commercial vehicles can significantly impact QD penetration in both mouse and human skin. Lotions that contain alpha hydroxyl acids (AHA) facilitated NP penetration. Lower QD signal was observed in skin studied using a Franz cell. Freshly excised human skin was also studied immediately after the sub-cutaneous fat removal process, then after 24 hours rest ex vivo. Resting human skin 24 hours prior to QD exposure significantly reduced epidermal presence. This study exemplifies how application vehicles, skin processing and the exposure protocol can affect QD penetration results and the conclusions that maybe drawn between skin models. PMID:27453793

  7. Iontophoresis itself on hairless mouse skin induces the loss of the epidermal calcium gradient without skin barrier impairment.

    PubMed

    Lee, S H; Choi, E H; Feingold, K R; Jiang, S; Ahn, S K

    1998-07-01

    Iontophoresis increases the delivery of drugs across the stratum corneum, but the pathway by which ionized drugs transit the stratum corneum is unknown. In this study we examined the effect of iontophoresis on the skin barrier and the epidermal calcium gradient. Hairless mice were subjected to iontophoresis for 5-120 min and skin specimens were prepared for electron microscopy. Neither positive nor negative iontophoresis affected transepidermal water loss. Lacunar dilatation and partial distention of the intercellular layers of the stratum corneum were observed in rough proportion to applied time in iontophoresis skin as well as control skin. Additionally, using calcium capture cytochemistry, we demonstrated that both positive and negative iontophoresis caused the disappearance of the epidermal calcium gradient with marked decrease in calcium content in the upper epidermis. Positive iontophoresis was associated with increased calcium in the stratum basale and dermis, whereas negative iontophoresis increased calcium in the stratum corneum. Moreover, as previously shown after barrier disruption and sonophoresis, the decrease in calcium content in the upper epidermis was associated with an increase in lamellar body secretion and the build up of lamellar material at the stratum corneum-stratum granulosum interface. In conclusion, iontophoresis on the skin of hairless mice may induce the change of ionized molecules in the epidermis, as the loss of the calcium gradient, which causes the decrease of skin impedence, gives charged drugs the ability to cross the skin more easily. Also, the structural changes, such as lacunar dilatation, whether they result from hydration or occlusion, may help the transport of charged drugs across the stratum corneum.

  8. Th1/Th2 balance in mouse delayed-type hypersensitivity model with mercuric chloride via skin and oral mucosa.

    PubMed

    Ukichi, Kenichirou; Okamura, Taito; Fukushima, Daihei; Morimoto, Mitsuaki; Yamane, Gen-Yuki; Takahashi, Shinichi

    2011-01-01

    In order to compare delayed-type hypersensitivity (DTH) among different exposure sites, we evaluated the sensitization potency of mercuric chloride (HgCl(2)) via exposure to the skin, or oral or esophageal mucosa using the mouse ear swelling test. Furthermore, we investigated in vitro splenocyte proliferation reaction and cytokine profile in HgCl(2)-exposed and control mice. Sensitization with HgCl(2) was established via the skin and oral mucosa but not via the esophageal mucosa. The splenocyte proliferation reaction was significantly enhanced to a similar degree in skin and oral mucosa-sensitized mice compared with in the control mice. IL-10 levels from cultured splenocytes were significantly increased in skin and oral mucosa-sensitized mice compared with those in control mice, whilst IFN-γ significantly increased only in splenocytes from skin-sensitized mice. These results suggest that exposure of the skin or oral mucosa to HgCl(2) can induce DTH, but that Th1/Th2 balance differs according to the site of antigen exposure.

  9. Continuous imaging of the blood vessels in tumor mouse dorsal skin window chamber model by using SD-OCT

    NASA Astrophysics Data System (ADS)

    Peng, Xiao; Yang, Shaozhuang; Yu, Bin; Wang, Qi; Lin, Danying; Gao, Jian; Zhang, Peiqi; Ma, Yiqun; Qu, Junle; Niu, Hanben

    2016-03-01

    Optical Coherence Tomography (OCT) has been widely applied into microstructure imaging of tissues or blood vessels with a series of advantages, including non-destructiveness, real-time imaging, high resolution and high sensitivity. In this study, a Spectral Domain OCT (SD-OCT) system with higher sensitivity and signal-to-noise ratio (SNR) was built up, which was used to observe the blood vessel distribution and blood flow in the dorsal skin window chamber of the nude mouse tumor model. In order to obtain comparable data, the distribution images of blood vessels were collected from the same mouse before and after tumor injection. In conclusion, in vivo blood vessel distribution images of the tumor mouse model have been continuously obtained during around two weeks.

  10. Effects of chronic low-dose ultraviolet B radiation on DNA damage and repair in mouse skin.

    PubMed

    Mitchell, D L; Greinert, R; de Gruijl, F R; Guikers, K L; Breitbart, E W; Byrom, M; Gallmeier, M M; Lowery, M G; Volkmer, B

    1999-06-15

    Chronic exposure to sunlight causes skin cancer in humans, yet little is known about how habitual exposure to low doses of ultraviolet B radiation (UVB) affects DNA damage in the skin. We treated Skh-1 hairless mice with daily doses of suberythemal UVB for 40 days and analyzed the amount and distribution of DNA photodamage using RIAs and immunofluorescence micrography. We found that DNA damage accumulated in mouse skin as a result of chronic irradiation and that this damage persisted in the dermis and epidermis for several weeks after the chronic treatment was terminated. Although the persistent damage was evenly distributed throughout the dermis, it remained in the epidermis as a small number of heavily damaged cells at the dermal-epidermal boundary. Rates of DNA damage induction and repair were determined at different times over the course of chronic treatment in response to a higher challenge dose of UVB light. The amount of damage induced by the challenge dose increased in response to chronic exposure, and excision repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone dimers was significantly reduced. The sensitization of mouse epidermal DNA to photoproduct induction, the reduction in excision repair, and the accumulation of nonrepairable DNA damage in the dermis and epidermis suggest that chronic low-dose exposure to sunlight may significantly enhance the predisposition of mammalian skin to sunlight-induced carcinogenesis.

  11. Cholera toxin, a potent inducer of epidermal hyperplasia but with no tumor promoting activity in mouse skin carcinogenesis

    SciTech Connect

    Kuroki, T.; Chida, K.; Munakata, K.; Murakami, Y.

    1986-05-29

    Intracutaneous injection of cholera toxin into mice induced epidermal hyperplasia to a greater extent than 12-O-tetra-decanoylphorbol-13-acetate. It also induced adenylate cyclase and through weakly, ornithine decarboxylase of the epidermis. Cholera toxin, however, showed no tumor promoting activity in mouse skin carcinogenesis. In the single stage promotion, cholera toxin (50 ng) was injected once a week for 10 weeks into the skin of SENCAR mice initiated with 25 ..mu..g 7,12-dimethyl-benz(a)anthracene, but no tumors developed. In the two-stage promotion test, cholera toxin (10-100 ng) was injected for one or two weeks into the initiated skin and then mezerein (4 ..mu..g) was applied twice a week for 18 weeks, but the toxin did not increase incidence or numbers of papillomas.

  12. Immunochemical and molecular characterization of anti-RNA polymerase I autoantibodies produced by tight skin mouse.

    PubMed Central

    Shibata, S; Muryoi, T; Saitoh, Y; Brumeanu, T D; Bona, C A; Kasturi, K N

    1993-01-01

    Autoantibodies against nuclear proteins like RNA polymerase I (RNA pol I) are produced in a number of rheumatic autoimmune diseases. Production of antibodies specific for the 190-kD subunit of RNA pol I appears to be characteristic in the patients with systemic sclerosis. Previous investigations have shown that the tight skin (TSK) mouse is an experimental model for systemic sclerosis. In the present study we show that the TSK mice produce high titers of anti-RNA pol I antibodies, both of IgM and IgG classes. To characterize the immunochemical properties of these antibodies we obtained a large panel of hybridomas from these mice. Analysis of these hybridomas revealed that clonal frequency of autoreactive B cells specific for RNA pol I are higher in the TSK mice that in the controls. mAbs obtained from the TSK mice were specific for the 190-kD subunit and cross-reacted with Escherichia coli and phage T7 RNA polymerases (155-, 150-, and 107-kD polypeptides). We have also demonstrated that these antibodies bind better to the phosphorylated enzymes. The anti-RNA pol I mAbs were divided into three groups in terms of their functional property. The first group of antibodies increased the catalytic activity of the enzyme whereas the antibodies of the second group inhibited the enzymatic activity. Competitive inhibition RIAs showed that these two groups of antibodies bound to distinct epitopes. The third group of antibodies was neutral and had no activity on the enzyme function. These results suggest that TSK mouse anti-RNA pol I antibodies recognize three or more conserved epitopes. To understand the molecular basis of the generation of such autoreactive antibodies we analyzed their V gene repertoire. Northern analysis of RNAs of 14 TSK hybridomas showed that the VH genes encoding these antibodies were mainly from VH J558 family. It is possible that these genes were derived from a single germline gene or from a set of related genes of a single subgroup. Images PMID:8349828

  13. Effects of the co-carcinogen catechol on benzo(a)pyrene metabolism and DNA adduct formation in mouse skin

    SciTech Connect

    Melikian, A.A.; Leszczynska, J.M.; Hecht, S.S.; Hoffmann, D.

    1986-01-01

    We have studied the effects of the co-carcinogen catechol (1,2-dihydroxybenzene) on the metabolic activation of (/sup 3/H) benzo(a)pyrene (BaP) in mouse skin, in vivo and on the binding of BaP metabolites to DNA and protein at intervals from 0.5-24 h. Upon topical application of 0.015 mg (/sup 3/H)BaP and 0.25 or 0.5 mg catechol per mouse, catechol had little effect on the total amount of (/sup 3/H)BaP metabolized in mouse skin, but it affected the relative proportions of (/sup 3/H)BaP metabolites. Catechol (0.5 mg/mouse) decreased the proportion of water-soluble (/sup 3/H)BaP metabolites, ethyl acetate-soluble polar metabolites and quinones, but doubled the levels of unconjugated 3-hydroxy-BaP at all measured intervals after treatment. Catechol also caused a small increase in the levels of trans-7,8-dihydroxy-7,8-dihydroBaP and trans-9,10-dihydroxy-9,10-dihydroBaP 0.5 h after treatment. Two hours after treatment, the levels of these metabolites subsided to those of the controls. Catechol did not affect the levels of glutathione conjugates of BaP. However, it caused a decrease in glucuronide and sulphate conjugate formation from BaP. Catechol caused an approximately 2-fold increase in the formation of anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydroBaP (BPDE) DNA adducts and elevated the ratio of anti-syn-BPDE-DNA adducts 1.6 to 2.9-fold. Catechol treatment increased the radioactivity associated with epidermal proteins after (/sup 3/H)BaP application. Because catechol increased levels of 3-hydroxyBaP, we considered the possibility that 3-hydroxyBaP might enhance the tumor initiating activities of BaP or BPDE in mouse skin; a bioassay demonstrated that this was not the case. The results of this study indicate that one important effect of catechol related to its co-carcinogenicity is its ability to enhance formation of anti-BPDE-DNA adducts in mouse skin.

  14. CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development.

    PubMed

    Macias, Everardo; Miliani de Marval, Paula L; De Siervi, Adriana; Conti, Claudio J; Senderowicz, Adrian M; Rodriguez-Puebla, Marcelo L

    2008-08-01

    It has been widely assumed that elevated CDK2 kinase activity plays a contributory role in tumorigenesis. We have previously shown that mice overexpressing CDK4 under control of the keratin 5 promoter (K5CDK4 mice) develop epidermal hyperplasia and increased susceptibility to squamous cell carcinomas. In this model, CDK4 overexpression results in increased CDK2 activity associated with the noncatalytic function of CDK4, sequestration of p21(Cip1) and p27(Kip1). Furthermore, we have shown that ablation of Cdk2 reduces Ras-Cdk4 tumorigenesis, suggesting that increased CDK2 activity plays an important role in Ras-mediated tumorigenesis. To investigate this hypothesis, we generated two transgenic mouse models of elevated CDK2 kinase activity, K5Cdk2 and K5Cdk4(D158N) mice. The D158N mutation blocks CDK4 kinase activity without interfering with its binding capability. CDK2 activation via overexpression of CDK4(D158N), but not of CDK2, resulted in epidermal hyperplasia. We observed elevated levels of p21(Cip1) in K5Cdk2, but not in K5Cdk4(D158N), epidermis, suggesting that CDK2 overexpression elicits a p21(Cip1) response to maintain keratinocyte homeostasis. Surprisingly, we found that neither CDK2 overexpression nor the indirect activation of CDK2 enhanced skin tumor development. Thus, although the indirect activation of CDK2 is sufficient to induce keratinocyte hyperproliferation, activation of CDK2 alone does not induce malignant progression in Ras-mediated tumorigenesis.

  15. DNA adducts in human and mouse skin maintained in short-term culture and treated with petrol and diesel engine lubricating oils.

    PubMed

    Carmichael, P L; Ni Shé, M; Phillips, D H

    1991-05-24

    Human and mouse skin samples maintained in short-term organ culture were treated topically with used engine oils from petrol- and diesel-powered vehicles. Mice were also treated topically in vivo for comparison. DNA was isolated and analysed by 32P-postlabelling and the labeled DNA digests were resolved on polyethyleneimine-cellulose tlc sheets. A large number of radioactive adduct spots were observed in DNA from skin treated with the used petrol-engine oil, indicating the formation of adducts by many components of the complex oil mixture. Total adduct levels were similar in mouse skin (both in vivo and in vitro) and in human skin, although qualitative differences in the adduct maps were apparent between the human and mouse skin DNA. Treatment with the used diesel engine oil produced adduct levels no greater than that of control samples in mouse skin (in vivo and in vitro), although significant levels were found in human skin DNA from one donor. The results correlate well with the carcinogenic activity of these oils in experimental animals, helping to substantiate the conclusion that petrol engine oils (but not diesel engine oils) may present a carcinogenic risk to man if appropriate measures to minimise skin contact are not observed.

  16. Recovery of Aging-Related Size Increase of Skin Epithelial Cells: In vivo Mouse and In vitro Human Study

    PubMed Central

    Sokolov, Igor; Guz, Natali V.; Iyer, Swaminathan; Hewitt, Amy; Sokolov, Nina A.; Erlichman, Joseph S.; Woodworth, Craig D.

    2015-01-01

    The size increase of skin epithelial cells during aging is well-known. Here we demonstrate that treatment of aging cells with cytochalasin B substantially decreases cell size. This decrease was demonstrated on a mouse model and on human skin cells in vitro. Six nude mice were treated by topical application of cytochalasin B on skin of the dorsal left midsection for 140 days (the right side served as control for placebo treatment). An average decrease in cell size of 56±16% resulted. A reduction of cell size was also observed on primary human skin epithelial cells of different in vitro age (passages from 1 to 8). A cell strain obtained from a pool of 6 human subjects was treated with cytochalasin B in vitro for 12 hours. We observed a decrease in cell size that became statistically significant and reached 20–40% for cells of older passage (6–8 passages) whereas no substantial change was observed for younger cells. These results may be important for understanding the aging processes, and for cosmetic treatment of aging skin. PMID:25807526

  17. Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis.

    PubMed Central

    Bianchi, A B; Navone, N M; Aldaz, C M; Conti, C J

    1991-01-01

    A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiation-promotion protocol, we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci. In a previous study, these tumors had been analyzed for their allelic composition at the Harvey ras-1 (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study, by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses, we detected complete loss of heterozygosity at the beta-globin (Hbb) locus, distal to Ha-ras-1, in 15 of 20 (75%) skin carcinomas. In addition, 5 of 5 informative cases attained homozygosity at the int-2 locus, 27 centimorgans distal to Hbb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus, demonstrating that this event occurs during premalignant stages of tumor development. Interestingly, loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric scanning of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-1 indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative

  18. Lgr6+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors

    PubMed Central

    van de Glind, Gerline C.; Rebel, Heggert G.; Out-Luiting, Jacoba J.; Zoutman, Wim; Tensen, Cornelis P.; de Gruijl, Frank R.

    2016-01-01

    Lgr6+ cells have been identified as a novel class of proliferating (Ki67+) stem cells in mouse epidermis. We investigated their response to UV exposure in Lgr6-EGFP-Ires-CreERT2/R26R-LacZ haired and hairless mice and whether they become initiating cells of UV- or chemically induced skin tumors. UV overexposure erased Lgr6+ cells (EGFP+) from the interfollicular epidermis (IFE), but - as after wounding - they apparently repopulated the IFE from the hair follicles. Under sub-sunburn chronic UV exposure, Lgr6+ cells and their progeny (LacZ+ after pulse of tamoxifen) diminished strongly in the IFE. Although the inter-tumoral IFE clearly showed Lgr6 progeny, none of the UV- or chemically induced tumors (n = 22 and 41, respectively) appeared to be clonal expansions of Lgr6+ stem cells; i.e. no Lgr6+ cells or progeny in the proliferating tumor bulk. In checking for promoter methylation we found it to occur stochastically for the EGFP-Cre cassette. Lgr6 mRNA measured by qPCR was found to be diminished in skin tumors (also in UV tumors from wt type mice). The ratio of Lgr6/Ki67 was significantly reduced, pointing at a loss of Lgr6+ cells from the proliferative pool. Our data show that Lgr6+ cells are not major tumor-initiating cells in skin carcinogenesis. PMID:27880932

  19. Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model.

    PubMed

    Nickoloff, B J; Kunkel, S L; Burdick, M; Strieter, R M

    1995-03-01

    Research into the cause and pathophysiological mechanisms underlying expression of psoriatric skin lesions has been hampered by lack of an appropriate animal model for this common and enigmatic cutaneous disease. These studies characterize normal skin, pre-psoriatic skin, and psoriatic plaque skin samples transplanted onto severe combined immunodeficiency mice. In this report we document that 1), normal, prepsoriatic, and psoriatic plaque keratome skin samples can be transplanted onto severe combined immunodeficiency mice reliably with high rates of graft survival (> 85%) and with reproducible changes consistently observed over prolonged periods of engraftment; 2), after transplantation, by clinical assessment and routine light microscopy, normal skin remained essentially normal whereas pre-psoriatic skin became thicker, and psoriatic plaque skin retained its characteristic plaque-type elevation and scale; 3), by using a panel of antibodies and immunohistochemical analysis, the overall phenotype of human cell types (including immunocytes) that persisted in the transplanted skin was remarkably similar to the immunophenotype of pretransplanted skin samples; 4), clearly recognized interface zones between human and murine skin within the epidermal and dermal compartments could be identified by routine microscopy and immunostaining, with focal areas of chimerism; and 5), elevated interleukin 8 cytokine levels were present in transplanted pre-psoriatic and psoriatic plaque skin samples. We conclude that there are many similarities between pre- and post-transplanted human samples of normal and psoriatic skin that are grafted onto severe combined immunodeficiency mice. Thus, we propose that this new animal model is appropriate for additional mechanistic-type studies designed to reveal the underlying genetic/etiological abnormality, as well as better illuminate the pathophysiological basis, for this important skin disease.

  20. Potent suppressive activity of pheophytin a and b from the non-polyphenolic fraction of green tea (Camellia sinensis) against tumor promotion in mouse skin.

    PubMed

    Higashi-Okai, K; Otani, S; Okai, Y

    1998-07-17

    Chlorophyll-related compounds pheophytin a and b have been recently identified as antigenotoxic substances in the non-polyphenolic fraction of green tea (Camellia sinensis), which suppressed umu C gene expression in tester bacteria induced by various genotoxins (Okai and Higashi-Okai, Cancer Lett. 118 (1997) 117-123). In the present study, the authors analyzed in vivo and in vitro effects of pheophytin a and b from the non-polyphenolic fraction of green tea on tumor promotion in mouse skin as follows. (1) When pheophytin a and b from green tea were topically applied prior to each treatment with a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) on BALB/c mouse skin initiated by 7,12 dimethylbenz[a]anthracene (DMBA), they caused suppression in a dose-dependent fashion against skin tumorigenesis. (2) Pheophytin a and b exhibited significant suppressions against TPA-induced inflammatory reaction, such as edema formation, in BALB/c mouse ear skin in a dose-dependent manner. (3) Pheophytin a and b from green tea showed inhibitory effects against early induction of ornithine decarboxylase (ODC) in BALB/c mouse skin fibroblasts caused by TPA. These results suggest that pheophytin a and b from the non-polyphenolic fraction have potent suppressive activities against tumor promotion in mouse skin.

  1. Inhibitory effects of chlorophyllin on 7,12-dimethylbenz[a]anthracene-induced bacterial mutagenesis and mouse skin carcinogenesis.

    PubMed

    Chung, W Y; Lee, J M; Park, M Y; Yook, J I; Kim, J; Chung, A S; Surh, Y J; Park, K K

    1999-10-18

    Chlorophyllin (CHL), a water-soluble derivative of chlorophyll, has been used for the treatment of several abnormal human conditions without apparent toxicity. Recent studies have revealed that CHL has the excellent chemopreventive potential. In the present investigation, we have found the inhibitory activities of CHL against 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in Salmonella typhimurium TA100 and also on DMBA-initiated and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-promoted mouse skin tumor formation. The incidence and the multiplicity of skin tumors were not significantly decreased in mice by a single topical application of CHL prior to the DMBA treatment, but there was a marked suppression of papillomagenesis in mice treated with CHL during the promotional stage. Furthermore, the formation of DMBA-induced papillomagenesis was reduced in all mice that had received CHL for 6 weeks following treatment with TPA for 6, 18 and 24 weeks. These results indicate that CHL can inhibit both tumor promotion and the progression of papillomagenesis in the two-stage mouse skin carcinogenesis induced by DMBA and TPA.

  2. FATAL KERATOMAS DUE TO DEEP HOMOGRAFTS OF THE BENIGN PAPILLOMAS OF TARRED MOUSE SKIN

    PubMed Central

    Rous, Peyton; Allen, Raymond A.

    1958-01-01

    enlarging, fluid-filled cyst forms, with walls that are bare except where a stalked or cauliflower papilloma exists, projecting inwards. At last the cyst ruptures and a second dissecting cyst forms, also devoid of papilloma tissue; or else the overlying skin undergoes pressure necrosis, the cyst fluid escapes through a rent, and fatal infection ensues. All gradations exist between Type A and Type C. The cancers derivative from both exhibit a marked disability,—though invasive they are almost or quite unable to extend along bare connective tissue. The papillomas that are possessed of this faculty spread beyond them along the cyst wall, and kill the host through their unceasing activity. In collateral work a papilloma was transplanted that was found protruding from the external auditory canal of a mouse which had received an intramuscular injection of methylcholanthrene many months previously. The tumor is now in its 5th generation, after 15 months. The growths it forms are of Type A. All of the papillomas are functioning tumors, with their own cells as the functioning product. Their papilliferous shape, when on the skin, is due solely to inability of their cells to gain space in other ways. Intrinsically they are keratomas. The papillomas do well after transfer to deep situations because the growth of their cells is indirectly promoted, through favoring local conditions. No direct promotion takes place like that when the cells of prostatic and mammary tumors are stimulated to multiply by hormones. Doubtless many agents act in both ways, that is to say by dual promotion. PMID:13481256

  3. Cyclooxygenases in human and mouse skin and cultured human keratinocytes: association of COX-2 expression with human keratinocyte differentiation

    NASA Technical Reports Server (NTRS)

    Leong, J.; Hughes-Fulford, M.; Rakhlin, N.; Habib, A.; Maclouf, J.; Goldyne, M. E.

    1996-01-01

    Epidermal expression of the two isoforms of the prostaglandin H-generating cyclooxygenase (COX-1 and COX-2) was evaluated both by immunohistochemistry performed on human and mouse skin biopsy sections and by Western blotting of protein extracts from cultured human neonatal foreskin keratinocytes. In normal human skin, COX-1 immunostaining is observed throughout the epidermis whereas COX-2 immunostaining increases in the more differentiated, suprabasilar keratinocytes. Basal cell carcinomas express little if any COX-1 or COX-2 immunostaining whereas both isozymes are strongly expressed in squamous cell carcinomas deriving from a more differentiated layer of the epidermis. In human keratinocyte cultures, raising the extracellular calcium concentration, a recognized stimulus for keratinocyte differentiation, leads to an increased expression of both COX-2 protein and mRNA; expression of COX-1 protein, however, shows no significant alteration in response to calcium. Because of a recent report that failed to show COX-2 in normal mouse epidermis, we also looked for COX-1 and COX-2 immunostaining in sections of normal and acetone-treated mouse skin. In agreement with a previous report, some COX-1, but no COX-2, immunostaining is seen in normal murine epidermis. However, following acetone treatment, there is a marked increase in COX-1 expression as well as the appearance of significant COX-2 immunostaining in the basal layer. These data suggest that in human epidermis as well as in human keratinocyte cultures, the expression of COX-2 occurs as a part of normal keratinocyte differentiation whereas in murine epidermis, its constitutive expression is absent, but inducible as previously published.

  4. Severe combined immunodeficiency mouse-human skin chimeras: a unique animal model for the study of psoriasis and cutaneous inflammation.

    PubMed

    Raychaudhuri, S P; Dutt, S; Raychaudhuri, S K; Sanyal, M; Farber, E M

    2001-05-01

    Elucidation of the molecular and cellular mechanisms responsible for the pathogenesis of psoriasis had been significantly handicapped due to lack of an ideal animal model. To overcome this hurdle several investigators have developed a number of animal models for psoriasis. Recent establishment of the SCID-human skin chimeras with transplanted psoriasis plaques has opened new vistas to study the molecular complexities involved in psoriasis. This model also offers a unique opportunity to investigate various key biological events such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. The SCID mouse model will be of immense help to target the cellular and molecular events associated with these pathogenic processes and develop novel drugs for psoriasis and other inflammatory diseases. In this article we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.

  5. Topical application of nitrosonifedipine, a novel radical scavenger, ameliorates ischemic skin flap necrosis in a mouse model.

    PubMed

    Fukunaga, Yutaka; Izawa-Ishizawa, Yuki; Horinouchi, Yuya; Sairyo, Eriko; Ikeda, Yasumasa; Ishizawa, Keisuke; Tsuchiya, Koichiro; Abe, Yoshiro; Hashimoto, Ichiro; Tamaki, Toshiaki

    2017-01-16

    Ischemic skin flap necrosis can occur in random pattern flaps. An excess amount of reactive oxygen species is generated and causes necrosis in the ischemic tissue. Nitrosonifedipine (NO-NIF) has been demonstrated to possess potent radical scavenging ability. However, there has been no study on the effects of NO-NIF on ischemic skin flap necrosis. Therefore, they evaluated the potential of NO-NIF in ameliorating ischemic skin flap necrosis in a mouse model. A random pattern skin flap (1.0 × 3.0 cm) was elevated on the dorsum of C57BL/6 mice. NO-NIF was administered by topical injection immediately after surgery and every 24 hours thereafter. Flap survival was evaluated on postoperative day 7. Tissue samples from the skin flaps were harvested on postoperative days 1 and 3 to analyze oxidative stress, apoptosis and endothelial dysfunction. The viable area of the flap in the NO-NIF group was significantly increased (78.30 ± 7.041%) compared with that of the control group (47.77 ± 6.549%, p < 0.01). NO-NIF reduced oxidative stress, apoptosis and endothelial dysfunction, which were evidenced by the decrease of malondialdehyde, p22phox protein expression, number of apoptotic cells, phosphorylated p38 MAPK protein expression, and vascular cell adhesion molecule-1 protein expression while endothelial nitric oxide synthase protein expression was increased. In conclusion, they demonstrated that NO-NIF ameliorated ischemic skin flap necrosis by reducing oxidative stress, apoptosis, and endothelial dysfunction. NO-NIF is considered to be a candidate for the treatment of ischemic flap necrosis.

  6. Induction of apoptosis by calcium D-glucarate in 7,12-dimethyl benz [a] anthracene-exposed mouse skin.

    PubMed

    Singh, Jaya; Gupta, Krishna P

    2007-01-01

    Calcium glucarate (Cag), a naturally occurring nontoxic compound, suppresses the DMBA-induced tumor development in mouse skin. In the process of understanding the mechanisms of tumor suppression by Cag, we investigated the effect of topical application of Cag on selective and critical events of apoptotic pathway in DMBA-exposed mouse epidermis. Varied doses of DMBA or Cag were used for the study. DMBA had an inhibitory effect on proteases in general and on caspases in particular. Cag tried to reverse the inhibitory effect of DMBA on 3, 8, or 9 caspase in a dose-dependent manner. Cag inhibited activity of Poly ADP-ribose polymerase enzyme, a substrate of caspses, after DMBA exposure. As indicated by western blotting, Cag treatment also inhibited PARP expression induced by DMBA at the level of protein. Cag induced the DMBA-inhibited Ca++/Mg++-dependent endonuclease, an enzyme responsible for the DNA fragmentation during apoptosis. DMBA induced the expression of mutant-p53 and Bcl-2. This induced expression of proteins was reversed when Cag was given along with DMBA. Cag showed a dose-dependent inhibition of DMBA-induced mutant-p53 expression. Similarly Bcl-2 overexpression by DMBA was also inhibited by topical treatment of Cag when given along with DMBA. Inhibition of mutant-p53 and Bcl-2 expression by Cag in DMBA-exposed mouse skin might contribute to the apoptogenic effect possibly exerted by Cag while suppressing the tumor development. The study indicates that Cag induces apoptosis in mouse epidermis, a possible mechanism for tumor suppression, and thus could be considered a promising anticancer agent.

  7. Efficient in vivo gene editing using ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model.

    PubMed

    Wu, Wenbo; Lu, Zhiwei; Li, Fei; Wang, Wenjie; Qian, Nannan; Duan, Jinzhi; Zhang, Yu; Wang, Fengchao; Chen, Ting

    2017-02-14

    The prokaryotic CRISPR/Cas9 system has recently emerged as a powerful tool for genome editing in mammalian cells with the potential to bring curative therapies to patients with genetic diseases. However, efficient in vivo delivery of this genome editing machinery and indeed the very feasibility of using these techniques in vivo remain challenging for most tissue types. Here, we show that nonreplicable Cas9/sgRNA ribonucleoproteins can be used to correct genetic defects in skin stem cells of postnatal recessive dystrophic epidermolysis bullosa (RDEB) mice. We developed a method to locally deliver Cas9/sgRNA ribonucleoproteins into the skin of postnatal mice. This method results in rapid gene editing in epidermal stem cells. Using this method, we show that Cas9/sgRNA ribonucleoproteins efficiently excise exon80, which covers the point mutation in our RDEB mouse model, and thus restores the correct localization of the collagen VII protein in vivo. The skin blistering phenotype is also significantly ameliorated after treatment. This study provides an in vivo gene correction strategy using ribonucleoproteins as curative treatment for genetic diseases in skin and potentially in other somatic tissues.

  8. Diffuse Optical Spectroscopy for the Quantitative Assessment of Acute Ionizing Radiation Induced Skin Toxicity Using a Mouse Model

    PubMed Central

    Chin, Lee; Korpela, Elina; Kim, Anthony; Yohan, Darren; Niu, Carolyn; Wilson, Brian C.; Liu, Stanley K.

    2016-01-01

    Acute skin toxicities from ionizing radiation (IR) are a common side effect from therapeutic courses of external beam radiation therapy (RT) and negatively impact patient quality of life and long term survival. Advances in the understanding of the biological pathways associated with normal tissue toxicities have allowed for the development of interventional drugs, however, current response studies are limited by a lack of quantitative metrics for assessing the severity of skin reactions. Here we present a diffuse optical spectroscopic (DOS) approach that provides quantitative optical biomarkers of skin response to radiation. We describe the instrumentation design of the DOS system as well as the inversion algorithm for extracting the optical parameters. Finally, to demonstrate clinical utility, we present representative data from a pre-clinical mouse model of radiation induced erythema and compare the results with a commonly employed visual scoring. The described DOS method offers an objective, high through-put evaluation of skin toxicity via functional response that is translatable to the clinical setting. PMID:27284926

  9. Efficient in vivo gene editing using ribonucleoproteins in skin stem cells of recessive dystrophic epidermolysis bullosa mouse model

    PubMed Central

    Wu, Wenbo; Lu, Zhiwei; Li, Fei; Wang, Wenjie; Qian, Nannan; Duan, Jinzhi; Zhang, Yu; Wang, Fengchao; Chen, Ting

    2017-01-01

    The prokaryotic CRISPR/Cas9 system has recently emerged as a powerful tool for genome editing in mammalian cells with the potential to bring curative therapies to patients with genetic diseases. However, efficient in vivo delivery of this genome editing machinery and indeed the very feasibility of using these techniques in vivo remain challenging for most tissue types. Here, we show that nonreplicable Cas9/sgRNA ribonucleoproteins can be used to correct genetic defects in skin stem cells of postnatal recessive dystrophic epidermolysis bullosa (RDEB) mice. We developed a method to locally deliver Cas9/sgRNA ribonucleoproteins into the skin of postnatal mice. This method results in rapid gene editing in epidermal stem cells. Using this method, we show that Cas9/sgRNA ribonucleoproteins efficiently excise exon80, which covers the point mutation in our RDEB mouse model, and thus restores the correct localization of the collagen VII protein in vivo. The skin blistering phenotype is also significantly ameliorated after treatment. This study provides an in vivo gene correction strategy using ribonucleoproteins as curative treatment for genetic diseases in skin and potentially in other somatic tissues. PMID:28137859

  10. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo.

    PubMed

    Kundu, Joydeb Kumar; Liu, Lijia; Shin, Jun-Wan; Surh, Young-Joon

    2013-09-06

    Thymoquinone (TQ), the active ingredient of Nigella sativa, has been reported to possess anti-inflammatory and chemopreventive properties. The present study was aimed at elucidating the molecular mechanisms of anti-inflammatory and antioxidative activities of thymoquinone in mouse skin. Pretreatment of female HR-1 hairless mouse skin with TQ attenuated 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2). TQ diminished nuclear translocation and the DNA binding of nuclear factor-kappaB (NF-κB) via the blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Pretreatment with TQ attenuated the phosphorylation of Akt, c-Jun-N-terminal kinase and p38 mitogen-activated protein kinase, but not that of extracellular signal-regulated kinase-1/2. Moreover, topical application of TQ induced the expression of heme oxygenase-1, NAD(P)H-quinoneoxidoreductase-1, glutathione-S-transferase and glutamate cysteine ligase in mouse skin. Taken together, the inhibitory effects of TQ on TPA-induced COX-2 expression and NF-κB activation, and its ability to induce the expression of cytoprotective proteins provide a mechanistic basis of anti-inflammatory and antioxidative effects of TQ in hairless mouse skin.

  11. DOSE-RESPONSE STUDIES OF SODIUM ARSENITE IN THE SKIN OF K6/ODC TRANSGENIC MOUSE

    EPA Science Inventory

    It has previously been observed that chronic exposure to inorganic arsenic and/or its metabolites increase(s) tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, gene expression profiles w...

  12. Proteomics of Skin Proteins in Psoriasis: From Discovery and Verification in a Mouse Model to Confirmation in Humans*

    PubMed Central

    Lundberg, Kathleen C.; Fritz, Yi; Johnston, Andrew; Foster, Alexander M.; Baliwag, Jaymie; Gudjonsson, Johann E.; Schlatzer, Daniela; Gokulrangan, Giridharan; McCormick, Thomas S.; Chance, Mark R.; Ward, Nicole L.

    2015-01-01

    Herein, we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n = 3) were compared with littermate controls (n = 3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average p = 0.0082; cystatin A, human ortholog); slc25a5 (average fold change of 46.2 and an average p = 0.0318); serpinb3b (average fold change of 35.6 and an average p = 0.0345; serpinB1, human ortholog); and kallikrein related peptidase 6 (average fold change of 4.7 and an average p = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, p < 0.0001), KLK6 (9-fold, p = 0.002), stefin A1 (7.3-fold; p < 0.001), and slc25A5 (1.5-fold; p = 0.05) using qRT-PCR on a second cohort of animals (n = 8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; p < 0.05), 29,000-fold (stefinA1; p < 0.01), 322-fold (KLK6; p < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes versus healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3-fold), KLK6 (5.8-fold), and serpinB1 (76-fold; all p < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover, slc25a5, cystatin A, KLK6, and serpinB1 protein were all increased in lesional psoriasis skin compared with normal skin. These results highlight the

  13. Proteomics of skin proteins in psoriasis: from discovery and verification in a mouse model to confirmation in humans.

    PubMed

    Lundberg, Kathleen C; Fritz, Yi; Johnston, Andrew; Foster, Alexander M; Baliwag, Jaymie; Gudjonsson, Johann E; Schlatzer, Daniela; Gokulrangan, Giridharan; McCormick, Thomas S; Chance, Mark R; Ward, Nicole L

    2015-01-01

    Herein, we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n = 3) were compared with littermate controls (n = 3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average p = 0.0082; cystatin A, human ortholog); slc25a5 (average fold change of 46.2 and an average p = 0.0318); serpinb3b (average fold change of 35.6 and an average p = 0.0345; serpinB1, human ortholog); and kallikrein related peptidase 6 (average fold change of 4.7 and an average p = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, p < 0.0001), KLK6 (9-fold, p = 0.002), stefin A1 (7.3-fold; p < 0.001), and slc25A5 (1.5-fold; p = 0.05) using qRT-PCR on a second cohort of animals (n = 8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; p < 0.05), 29,000-fold (stefinA1; p < 0.01), 322-fold (KLK6; p < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes versus healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3-fold), KLK6 (5.8-fold), and serpinB1 (76-fold; all p < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover, slc25a5, cystatin A, KLK6, and serpinB1 protein were all increased in lesional psoriasis skin compared with normal skin. These results highlight the

  14. Harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects.

    PubMed

    Yanagi, Teruki; Akiyama, Masashi; Nishihara, Hiroshi; Sakai, Kaori; Nishie, Wataru; Tanaka, Shinya; Shimizu, Hiroshi

    2008-10-01

    Harlequin ichthyosis (HI), which is the most severe genodermatosis, is caused by loss-of-function mutations in ABCA12, a member of the ATP-binding cassette transporter family. To investigate the pathomechanism of HI and the function of the ABCA12 protein, we generated ABCA12-deficient mice (Abca12(-/-)) by targeting Abca12. Abca12(-/-) mice closely reproduce the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure. Lamellar granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assay of Abca12(-/-) fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, the Abca12(-/-) mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells of the Abca12(-/-) mice lacked normal lamellar structures. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12(-/-) mice. Fetal therapeutic trials with systemic administration of retinoid or dexamethasone, which are effective for HI and respiratory distress, respectively, to the pregnant mother mice neither improved the skin phenotype nor extended the survival period. Our HI model mice reproduce the human HI skin phenotype soon after the initiation of fetal skin keratinization and provide evidence that ABCA12 plays pivotal roles in lung and skin barrier functions.

  15. Berteroin Present in Cruciferous Vegetables Exerts Potent Anti-Inflammatory Properties in Murine Macrophages and Mouse Skin

    PubMed Central

    Jung, Yoo Jin; Jung, Jae In; Cho, Han Jin; Choi, Myung-Sook; Sung, Mi-Kyung; Yu, Rina; Kang, Young-Hee; Park, Jung Han Yoon

    2014-01-01

    Berteroin (5-methylthiopentyl isothiocyanate) is a sulforaphane analog present in cruciferous vegetables, including Chinese cabbage, rucola salad leaves, and mustard oil. We examined whether berteroin exerts anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophages and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin inflammation models. Berteroin decreased LPS-induced release of inflammatory mediators and pro-inflammatory cytokines in Raw 264.7 macrophages. Berteroin inhibited LPS-induced degradation of inhibitor of κBα (IκBα) and nuclear factor-κB p65 translocation to the nucleus and DNA binding activity. Furthermore, berteroin suppressed degradation of IL-1 receptor-associated kinase and phosphorylation of transforming growth factor β activated kinase-1. Berteroin also inhibited LPS-induced phosphorylation of p38 MAPK, ERK1/2, and AKT. In the mouse ear, berteroin effectively suppressed TPA-induced edema formation and down-regulated iNOS and COX-2 expression as well as phosphorylation of AKT and ERK1/2. These results demonstrate that berteroin exhibits potent anti-inflammatory properties and suggest that berteroin can be developed as a skin anti-inflammatory agent. PMID:25393510

  16. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog.

    PubMed

    Abel, E L; Boulware, S; Fields, T; McIvor, E; Powell, K L; DiGiovanni, J; Vasquez, K M; MacLeod, M C

    2013-02-01

    Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.

  17. Suppressive Effect of Dietary Fucoidan on Proinflammatory Immune Response and MMP-1 Expression in UVB-Irradiated Mouse Skin.

    PubMed

    Maruyama, Hiroko; Tamauchi, Hidekazu; Kawakami, Fumitaka; Yoshinaga, Keiko; Nakano, Takahisa

    2015-10-01

    It is well known that ultraviolet B irradiation leads to dermal inflammation. In this study, we found that Mekabu fucoidan suppressed edema, decreased the thickness of the prickle cell layer, and decreased matrix metalloproteinase 1 in the skin of mice irradiated with ultraviolet B. Moreover, we found that the mean level of interferon gamma of Mekabu fucoidan-treated, ultraviolet B-irradiated mice (approximately 2.2 ng/mL) was not significantly different from that in normal mice (approximately 2.5 ng/mL). In contrast, a significant decrease in the mean level of interferon gamma (approximately 1.3 ng/mL) in ultraviolet B-irradiated control mice was observed compared with that in Mekabu fucoidan-treated, ultraviolet B-irradiated mice. The mean thickness of the prickle cell layer in the skin of Mekabu fucoidan-treated, ultraviolet B-irradiated mice was less than that in the ultraviolet B-irradiated control mice. Metalloproteinase 1 activity was significantly higher in the skin of ultraviolet B-irradiated mice than in the skin of untreated, nonirradiated normal mice. Metalloproteinase 1 in the skin of ultraviolet B-irradiated, Mekabu fucoidan- or L(+)-ascorbic acid (vitamin C)-treated mice was significantly lower than that in the ultraviolet B-irradiated control mice. Mitigation of the morphological changes in Mekabu fucoidan-treated mice was correlated with a decrease in metalloproteinase 1 levels. These data indicate that Mekabu fucoidan is an effective suppressor of inflammation in an ultraviolet B-irradiated mouse model.

  18. MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a.

    PubMed

    Zhao, Yuanyuan; Wang, Pengchao; Meng, Jinzhu; Ji, Yuankai; Xu, Dongmei; Chen, Tianzhi; Fan, Ruiwen; Yu, Xiuju; Yao, Jianbo; Dong, Changsheng

    2015-05-14

    MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a-3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post-transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced β-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression.

  19. A Novel Nude Mouse Model of Hypertrophic Scarring Using Scratched Full Thickness Human Skin Grafts

    PubMed Central

    Alrobaiea, Saad M.; Ding, Jie; Ma, Zengshuan; Tredget, Edward E.

    2016-01-01

    Objective: Hypertrophic scar (HTS) is a dermal form of fibroproliferative disorder that develops following deep skin injury. HTS can cause deformities, functional disabilities, and aesthetic disfigurements. The pathophysiology of HTS is not understood due to, in part, the lack of an ideal animal model. We hypothesize that human skin with deep dermal wounds grafted onto athymic nude mice will develop a scar similar to HTS. Our aim is to develop a representative animal model of human HTS. Approach: Thirty-six nude mice were grafted with full thickness human skin with deep dermal scratch wound before or 2 weeks after grafting or without scratch. The scratch on the human skin grafts was made using a specially designed jig that creates a wound >0.6 mm in depth. The xenografts were morphologically analyzed by digital photography. Mice were euthanized at 1, 2, and 3 months postoperatively for histology and immunohistochemistry analysis. Results: The mice developed raised and firm scars in the scratched xenografts with more contraction, increased infiltration of macrophage, and myofibroblasts compared to the xenografts without deep dermal scratch wound. Scar thickness and collagen bundle orientation and morphology resembled HTS. The fibrotic scars in the wounded human skin were morphologically and histologically similar to HTS, and human skin epithelial cells persisted in the remodeling tissues for 1 year postengraftment. Innovation and Conclusions: Deep dermal injury in human skin retains its profibrotic nature after transplantation, affording a novel model for the assessment of therapies for the treatment of human fibroproliferative disorders of the skin. PMID:27366591

  20. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin.

    PubMed

    Kunta, J R; Goskonda, V R; Brotherton, H O; Khan, M A; Reddy, I K

    1997-12-01

    The potential use of terpenes/terpenoids as penetration enhancers in the transdermal delivery of propranolol hydrochloride (PL) was investigated. PL was chosen for the reasons of its extensive first-pass metabolism and short elimination half-life. The terpenes studied included L-menthol, (+)-limonene, (+/-)-linalool, and carvacrol at 1%, 5%, and 10% w/v concentrations. The diffusion of PL across excised hairless mouse skin was determined using side-by-side diffusion cells. Flux, permeability coefficient (Pm), and lag time (tL) were calculated. PL showed comparable lag times with menthol at all three concentration levels. At a 1% level of carvacrol, PL exhibited a 2.4- and 2.2-fold increase in lag time compared with 5 and 10% levels of enhancer, respectively. In the presence of limonene, PL had shown maximum lag time (between 3.0 and 3.3 h) at all three levels. In the case of linalool, the lag times for PL with 5 and 10% levels of enhancer were 7.0- and 5.2-fold less compared with 1% level. A significant (p < 0.05) concentration effect was observed only with linalool. Hydrogel-based patches were formulated with or without menthol as enhancer. Release profiles from the hydrogel formulations obeyed zero-order kinetics. The permeability of propranolol was significantly higher (p < 0.05) from the test patch than the control (no enhancer) patch across the mouse skin. The mechanism of permeation enhancement of menthol could involve its distribution preferentially into the intercellular spaces of stratum corneum and the possible reversible disruption of the intercellular lipid domain. The results suggest the potential use of menthol as effective penetration enhancer in the delivery of significant amounts of PL through skin.

  1. Phytosphingosine stimulates the differentiation of human keratinocytes and inhibits TPA-induced inflammatory epidermal hyperplasia in hairless mouse skin.

    PubMed

    Kim, Sujong; Hong, Il; Hwang, Jung Sun; Choi, Jin Kyu; Rho, Ho Sik; Kim, Duck Hee; Chang, Ihseop; Lee, Seung Hun; Lee, Mi-Ock; Hwang, Jae Sung

    2006-01-01

    The binding of sphingoid bases to peroxisome proliferator-activated receptor (PPAR) has been detected in a solid-phase binding assay. However, sphingoid base-induced changes in PPAR transactivation activity have not been examined. In this report, we show by reporter gene analyses that phytosphingosine (PS), a natural sphingoid base, activates the transcriptional activity of PPARs in the immortalized human keratinocyte, HaCaT. Real-time PCR analyses showed that the mRNA level of PPARgamma was increased after PS treatment in HaCaT cells in a dose- and time-dependent manner. Because PPARs play important roles in skin barrier homeostasis by regulating epidermal cell growth, terminal differentiation, and inflammatory response, we examined the effect of PS on normal human epidermal keratinocytes (NHEKs) and mouse skin. PS increased the production of cornified envelope in NHEKs by approximately 1.8-fold compared with controls. Epidermal differentiation marker proteins such as involucrin, loricrin, and keratin1 were also increased in PS-treated NHEKs, by ELISA or Western blotting analysis. A [(3)H]thymidine incorporation assay showed that PS inhibited DNA synthesis in NHEKs to 20% compared with controls. The antiproliferative and anti-inflammatory effects of PS were examined in a mouse model of irritant contact dermatitis produced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA). PS blocked epidermal thickening and edema and the infiltration of inflammatory cells into the dermis in the skin of TPA-treated hairless mice. The anti-inflammatory effects of PS were confirmed by the observation that PS blocked the TPA-induced generation of prostaglandin E(2) in peripheral mononuclear leukocytes. Taken together, our results provide an insight into the multiple regulatory roles of PS in epidermal homeostasis, and furthermore point to the potential use of PS as a therapeutic agent in the treatment of inflammatory and proliferative cutaneous diseases.

  2. Phytosphingosine Stimulates the Differentiation of Human Keratinocytes and Inhibits TPA-Induced Inflammatory Epidermal Hyperplasia in Hairless Mouse Skin

    PubMed Central

    Kim, Sujong; Hong, Il; Hwang, Jung Sun; Choi, Jin Kyu; Rho, Ho Sik; Kim, Duck Hee; Chang, Ihseop; Lee, Seung Hun; Lee, Mi-Ock; Hwang, Jae Sung

    2006-01-01

    The binding of sphingoid bases to peroxisome proliferator-activated receptor (PPAR) has been detected in a solid-phase binding assay. However, sphingoid base–induced changes in PPAR transactivation activity have not been examined. In this report, we show by reporter gene analyses that phytosphingosine (PS), a natural sphingoid base, activates the transcriptional activity of PPARs in the immortalized human keratinocyte, HaCaT. Real-time PCR analyses showed that the mRNA level of PPARγ was increased after PS treatment in HaCaT cells in a dose- and time-dependent manner. Because PPARs play important roles in skin barrier homeostasis by regulating epidermal cell growth, terminal differentiation, and inflammatory response, we examined the effect of PS on normal human epidermal keratinocytes (NHEKs) and mouse skin. PS increased the production of cornified envelope in NHEKs by approximately 1.8-fold compared with controls. Epidermal differentiation marker proteins such as involucrin, loricrin, and keratin1 were also increased in PS-treated NHEKs, by ELISA or Western blotting analysis. A [3H]thymidine incorporation assay showed that PS inhibited DNA synthesis in NHEKs to 20% compared with controls. The antiproliferative and anti-inflammatory effects of PS were examined in a mouse model of irritant contact dermatitis produced by topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA). PS blocked epidermal thickening and edema and the infiltration of inflammatory cells into the dermis in the skin of TPA-treated hairless mice. The anti-inflammatory effects of PS were confirmed by the observation that PS blocked the TPA-induced generation of prostaglandin E2 in peripheral mononuclear leukocytes. Taken together, our results provide an insight into the multiple regulatory roles of PS in epidermal homeostasis, and furthermore point to the potential use of PS as a therapeutic agent in the treatment of inflammatory and proliferative cutaneous diseases. PMID:16838068

  3. Deoxynivalenol induced mouse skin tumor initiation: Elucidation of molecular mechanisms in human HaCaT keratinocytes.

    PubMed

    Mishra, Sakshi; Tewari, Prachi; Chaudhari, Bhushan P; Dwivedi, Premendra D; Pandey, Haushila P; Das, Mukul

    2016-11-01

    Among food contaminants, mycotoxins are toxic to both human and animal health. Our prior studies suggest that Deoxynivalenol (DON), a mycotoxin, behaves as a tumor promoter by inducing edema, hyperplasia, ODC activity and activation of MAPK's in mouse skin. In this study, topical application of DON, 336 and 672 nmol significantly enhanced ROS levels, DNA damage and apoptosis with concomitant downregulation of Ki-67, cyclin D, cyclin E, cyclin A and cyclin-dependent kinases (CDK4 and CDK2) thereby resulting in tumor initiation in mouse skin. Further, the elucidation of molecular mechanisms of tumor initiation by DON (0.42-3.37 nmol/ml) in HaCaT keratinocytes, revealed (i) enhanced ROS generation with cell cycle phase arrest in G0/G1 phase, (ii) increase in levels of 8-OxoG (6-24 hr) and γH2AX protein, (iii) significant enhancement in oxidative stress marker enzymes LPO, GSH, GR with concomitant decrease in antioxidant enzymes catalase, GPx, GST, SOD and mitochondrial membrane potential after DON (1.68 nmol) treatment, (iv) suppression of Nrf2 translocation to nucleus, enhanced phosphorylation with subsequent activation ERK1/2, p38 and JNK MAPK's following DON (1.68 nmol) treatment, (v) overexpression of c-jun, c-fos proteins, upregulation of Bax along with downregulation of Bcl-2 proteins, (vi) increase in cytochrome-c, caspase-9, caspase-3 and poly ADP ribose polymerase levels leads to apoptosis. Pretreatment of superoxide dismutase, mannitol and ethanol to HaCaT cells resulted in significant reduction in ROS levels and apoptosis indicating the role of superoxide and hydroxyl radicals in DON induced apoptosis as an early event and skin tumor initiation as a late event.

  4. Inhibitory effect of pheophorbide a, a chlorophyll-related compound, on skin tumor promotion in ICR mouse.

    PubMed

    Nakamura, Y; Murakami, A; Koshimizu, K; Ohigashi, H

    1996-11-29

    Anti-tumor-promoting activity of pheophorbide a (PPBa) a chlorophyll-related compound, was examined in a two-stage carcinogenesis experiment in ICR mouse skin by 7,12-dimethylbenz[a] anthracene (DMBA, 0.19 mumol) and 12-O-tetradecanoylphorbol-13-acetate (TPA, 1.6 nmol). Topical application of PPBa (160 nmol) markedly reduced the average number of tumors per mouse and the ratio of tumor-bearing mice (inhibitory ratio: IR = 56%, P < 0.01 and 31%, P < 0.005, respectively). PPBa exhibited potent anti-inflammatory activity in ICR mouse ears and moderate inhibitory activity toward TPA-induced superoxide (O2-) generation in differentiated HL-60 cells. While CuPPBa, a synthetic copper complex of PPBa, exhibited higher anti-inflammatory activity than that of indomethacin, it showed little antioxidative effect against formation of lipid hydroperoxides (LOOHs) and malondialdehyde (MDA), suggesting that the antioxidative effect of PPBa might not be important for anti-inflammatory activity. These results imply that the active mechanism of PPBa for anti-tumor promotion might be partly involved in inhibition of TPA-induced inflammatory responses by suppressing leukocyte activation.

  5. Topically applied ZnO nanoparticles suppress allergen induced skin inflammation but induce vigorous IgE production in the atopic dermatitis mouse model

    PubMed Central

    2014-01-01

    Background Metal oxide nanoparticles such as ZnO are used in sunscreens as they improve their optical properties against the UV-light that causes dermal damage and skin cancer. However, the hazardous properties of the particles used as UV-filters in the sunscreens and applied to the skin have remained uncharacterized. Methods Here we investigated whether different sized ZnO particles would be able to penetrate injured skin and injured allergic skin in the mouse atopic dermatitis model after repeated topical application of ZnO particles. Nano-sized ZnO (nZnO) and bulk-sized ZnO (bZnO) were applied to mechanically damaged mouse skin with or without allergen/superantigen sensitization. Allergen/superantigen sensitization evokes local inflammation and allergy in the skin and is used as a disease model of atopic dermatitis (AD). Results Our results demonstrate that only nZnO is able to reach into the deep layers of the allergic skin whereas bZnO stays in the upper layers of both damaged and allergic skin. In addition, both types of particles diminish the local skin inflammation induced in the mouse model of AD; however, nZnO has a higher potential to suppress the local effects. In addition, especially nZnO induces systemic production of IgE antibodies, evidence of allergy promoting adjuvant properties for topically applied nZnO. Conclusions These results provide new hazard characterization data about the metal oxide nanoparticles commonly used in cosmetic products and provide new insights into the dermal exposure and hazard assessment of these materials in injured skin. PMID:25123235

  6. Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of tenoxicam through hairless mouse skin.

    PubMed

    Gwak, Hye Sun; Chun, In Koo

    2002-04-02

    The effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from saturated solutions through dorsal hairless mouse skin were investigated. Various types of vehicles, including ester-, alcohol-, and ether-types and their mixtures, were used as vehicles, and then a series of fatty acids and amines were employed as enhancers, respectively. Even though the fluxes of tenoxicam from saturated pure vehicles were generally low (0.1-1.1 microg/cm2 per h), the skin permeability of tenoxicam was significantly increased by the combination of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) or propylene glycol monocaprylate (PGMC); the highest fluxes were achieved at 40% of DGME in both of the two cosolvents. The marked synergistic enhancement was also obtained by using propylene glycol (PG)-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. But saturated fatty acids failed to show a significant enhancing effect. The enhancement factors with the addition of oleic acid (OA) or linoleic acid (LOA) to PG were 348 and 238, respectively. Tromethamine (TM) showed an enhancing effect by the increased solubility; however, triethanolamine (TEA) did not show a significant enhancing effect. Rather, it decreased the fluxes of tenoxicam when added to PG with fatty acids. The above results indicate that the combinations of lipophilic vehicles like OA, LOA or OAl and hydrophilic vehicles like PG can be used for enhancing the skin permeation of tenoxicam.

  7. Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.

    PubMed

    Li, Yong; Stoll, Stefan W; Sekhon, Sahil; Talsma, Caroline; Camhi, Maya I; Jones, Jennifer L; Lambert, Sylviane; Marley, Hue; Rittié, Laure; Grachtchouk, Marina; Fritz, Yi; Ward, Nicole L; Elder, James T

    2016-03-01

    To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.

  8. Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands

    PubMed Central

    Li, Yong; Stoll, Stefan W.; Sekhon, Sahil; Talsma, Caroline; Camhi, Maya I.; Jones, Jennifer L.; Lambert, Sylviane; Marley, Hue; Rittié, Laure; Grachtchouk, Marina; Fritz, Yi; Ward, Nicole L.; Elder, James T.

    2016-01-01

    To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5′ and 3′ untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67+ cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67+ cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen. PMID:26519132

  9. Early changes produced in mouse skin by the application of three middle distillates.

    PubMed

    Grasso, P; Sharratt, M; Ingram, A J

    1988-01-01

    It has been reported by the American Petroleum Institute (API) that dermal applications of certain middle distillates of mineral oils can result in high incidences of skin tumours in mice. This was unexpected as the polycyclic aromatic hydrocarbon (PAH) levels in these were below detection limits. To examine the possible role of tissue injury in the induction of tumours, the skin reactions produced by thrice weekly applications of three middle distillates similar to those tested by the API were examined grossly and histopathologically at intervals up to 6 weeks. Various reference materials and oils were used as controls. Preliminary histological examination showed that severe skin damage was present from week 1 onwards in mice treated with the three middle distillates, two of them producing epidermal loss and ulceration. Marked epidermal hyperplasia was produced by all three middle distillates. These findings support the view that regenerative epidermal hyperplasia due to repeated severe skin damage may have exerted a powerful promotional effect in the production of the skin tumours by middle distillates in the API study.

  10. Akt/hypoxia-inducible factor-1α signaling deficiency compromises skin wound healing in a type 1 diabetes mouse model

    PubMed Central

    JING, LIFENG; LI, SHUANG; LI, QIN

    2015-01-01

    The aim of the present study was to investigate the mechanisms for impaired skin wound healing in subjects with diabetes. Type 1 diabetes (T1DM) was induced in BALB/c mice using streptozotocin. One month after the establishment of the T1DM mouse model, a wound was formed on the back of the mice, and tissues from the wounds and the margins were collected on days 0, 3, 7 and 10. Protein levels of cluster of differentiation 31 (CD31) were detected using immunohistochemistry, and the mRNA levels of Akt, hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor (Vegf), VEGF receptor 2 (Vegfr2), stromal cell-derived growth factor-1α (Sdf-1α) and CXC chemokine receptor 4 (Cxcr4) were determined using reverse transcription-quantitative polymerase chain reaction analysis. The corresponding protein levels were determined using western blotting. The skin wound healing rate in the T1DM mice was significantly lower than that in the control mice, and the protein level of CD31 in the wounded skin of the T1DM mice was significantly decreased. Furthermore, the overall mRNA levels of Akt, Hif-1α, Vegf, Vegfr2, Sdf-1α and Cxcr4 in the T1DM mice were significantly lower than those in the control mice, and similar trends were observed in the protein levels. In conclusion, skin wound healing was impaired in the T1DM mice, and this may have been caused by a deficiency of Akt/HIF-1α and downstream signaling, as well as delayed angiogenesis. PMID:26136949

  11. Alterations in Inflammatory Cytokine Gene Expression in Sulfur Mustard-Exposed Mouse Skin

    DTIC Science & Technology

    2000-01-01

    S. Proin- flammatory cytokines and their corresponding receptor proteins in eccrine sweat glands in normal and cutaneous leishmaniasis human skin...phosphoribosyltransferase (HPRT) was constructed using the PCR MIMIC Construction Kit (Clontech) ac- cording to the manufacturer’s instructions with the composite primers

  12. Optical Monitoring of Living Nerve Terminal Labeling in Hair Follicle Lanceolate Endings of the Ex Vivo Mouse Ear Skin

    PubMed Central

    Bewick, Guy S.; Banks, Robert W.

    2016-01-01

    A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs. control comparisons in the same ear from a single individual. Helpful tips are given for improving the quality of the preparation, the labeling and the imaging parameters. This new system is suitable for assaying pharmacologically and mechanically-induced uptake and release of these vital dyes in lanceolate terminals in both wild-type and genetically modified animals. Examples of modulatory influences on labeling intensity are given. PMID:27077818

  13. Monitoring changes in the scattering properties of mouse skin with optical coherence tomography during an in vivo glucose tolerance test

    NASA Astrophysics Data System (ADS)

    Kinnunen, M.; Tausta, S.; Myllylä, R.; Vainio, S.

    2007-05-01

    A non-invasive glucose monitoring technique would make evaluation of blood glucose values easier and more convenient. This would help diabetic patients to control their blood glucose values more regularly. A few years ago optical coherence tomography (OCT) was proposed as a non-invasive sensor for monitoring changes in blood glucose concentration. The method is based on monitoring glucose-induced changes in the scattering properties of the target. This article describes how OCT was used to monitor changes in the scattering properties of mouse skin during an in vivo glucose tolerance test. The results show that OCT has the potential to register glucose-induced changes in the optical properties of the sample. However, a commercial OCT device with a probe designed for imaging is not very suitable for non-invasive monitoring of glucose-induced changes in scattering. The problems confronted in this study, possibly originating from the small size of the animals, are discussed in the article.

  14. Optical Monitoring of Living Nerve Terminal Labeling in Hair Follicle Lanceolate Endings of the Ex Vivo Mouse Ear Skin.

    PubMed

    Bewick, Guy S; Banks, Robert W

    2016-04-05

    A novel dissection and recording technique is described for optical monitoring staining and de-staining of lanceolate terminals surrounding hair follicles in the skin of the mouse pinna. The preparation is simple and relatively fast, reliably yielding extensive regions of multiple labeled units of living nerve terminals to study uptake and release of styryl pyridinium dyes extensively used in studies of vesicle recycling. Subdividing the preparations before labeling allows test vs. control comparisons in the same ear from a single individual. Helpful tips are given for improving the quality of the preparation, the labeling and the imaging parameters. This new system is suitable for assaying pharmacologically and mechanically-induced uptake and release of these vital dyes in lanceolate terminals in both wild-type and genetically modified animals. Examples of modulatory influences on labeling intensity are given.

  15. Alterations in the expression of uvomorulin and Na+,K(+)-adenosine triphosphatase during mouse skin tumor progression.

    PubMed Central

    Ruggeri, B.; Caamano, J.; Slaga, T. J.; Conti, C. J.; Nelson, W. J.; Klein-Szanto, A. J.

    1992-01-01

    Uvomorulin (E-cadherin), a cell adhesion molecule, and Na+,K(+)-adenosine triphosphatase (ATPase), a marker protein of the basal-lateral cell membrane domains of polarized epithelial cells, were investigated in a group of mouse skin tumors induced by a two-stage chemical carcinogenesis protocol and in cell lines derived from mouse skin papillomas and squamous cell carcinomas (SCC). Although these two markers were present in benign tumors and in nontumorigenic cell lines, the Na+,K(+)-ATPase showed an altered pattern of distribution that included the presence of enzyme not only in the basolateral domain but also on the apical domain of the cell membrane of basal and spinous cells in well-differentiated squamous cell carcinomas (SCC). In higher grade SCC, a loss of Na+,K(+)-ATPase immunoreactivity was simultaneously detected with a marginal or absent expression of uvomorulin. The more differentiated SCC and papillomas expressed less uvomorulin immunoreactivity than normal epidermal cells. Both markers were seen in tumor cell lines that produced well-differentiated SCC after subcutaneous inoculation into nude mice. Neither Na+,K(+)-ATPase nor uvomorulin could be detected in cell lines that produced high grade, poorly differentiated SCC. Northern blots confirmed the absence of uvomorulin mRNA in these highly malignant cell lines. These data indicate that progression from premalignant papilloma to low-grade SCC and subsequently to high-grade SCC is accompanied by loss of epithelial cell polarity as detected by changes in Na+,K(+)-ATPase and by decreased or absent expression of uvomorulin in tumors and cell lines characterized by an advanced malignant phenotype. Images Figure 1 Figure 2 Figure 3 PMID:1316085

  16. Differential gene expression profiling of mouse skin after sulfur mustard exposure: Extended time response and inhibitor effect

    SciTech Connect

    Gerecke, Donald R. Chen Minjun; Isukapalli, Sastry S.; Gordon, Marion K.; Chang, Y.-C.; Tong Weida; Androulakis, Ioannis P.; Georgopoulos, Panos G.

    2009-01-15

    Sulfur mustard (HD, SM), is a chemical warfare agent that within hours causes extensive blistering at the dermal-epidermal junction of skin. To better understand the progression of SM-induced blistering, gene expression profiling for mouse skin was performed after a single high dose of SM exposure. Punch biopsies of mouse ears were collected at both early and late time periods following SM exposure (previous studies only considered early time periods). The biopsies were examined for pathological disturbances and the samples further assayed for gene expression profiling using the Affymetrix microarray analysis system. Principal component analysis and hierarchical cluster analysis of the differently expressed genes, performed with ArrayTrack showed clear separation of the various groups. Pathway analysis employing the KEGG library and Ingenuity Pathway Analysis (IPA) indicated that cytokine-cytokine receptor interaction, cell adhesion molecules (CAMs), and hematopoietic cell lineage are common pathways affected at different time points. Gene ontology analysis identified the most significantly altered biological processes as the immune response, inflammatory response, and chemotaxis; these findings are consistent with other reported results for shorter time periods. Selected genes were chosen for RT-PCR verification and showed correlations in the general trends for the microarrays. Interleukin 1 beta was checked for biological analysis to confirm the presence of protein correlated to the corresponding microarray data. The impact of a matrix metalloproteinase inhibitor, MMP-2/MMP-9 inhibitor I, against SM exposure was assessed. These results can help in understanding the molecular mechanism of SM-induced blistering, as well as to test the efficacy of different inhibitors.

  17. Hair Follicle Morphogenesis in the Treatment of Mouse Full-Thickness Skin Defects Using Composite Human Acellular Amniotic Membrane and Adipose Derived Mesenchymal Stem Cells

    PubMed Central

    Minjuan, Wu; Jun, Xiong; Shiyun, Shao; Sha, Xu; Haitao, Ni

    2016-01-01

    Early repair of skin injury and maximal restoration of the function and appearance have become important targets of clinical treatment. In the present study, we observed the healing process of skin defects in nude mice and structural characteristics of the new skin after transplantation of isolated and cultured adipose derived mesenchymal stem cells (ADMSCs) onto the human acellular amniotic membrane (AAM). The result showed that ADMSCs were closely attached to the surface of AAM and grew well 24 h after seeding. Comparison of the wound healing rate at days 7, 14, and 28 after transplantation showed that ADMSCs seeded on AAM facilitated the healing of full-thickness skin wounds more effectively as compared with either hAM or AAM alone, indicating that ADMSCs participated in skin regeneration. More importantly, we noticed a phenomenon of hair follicle development during the process of skin repair. Composite ADMSCs and AAM not only promoted the healing of the mouse full-thickness defects but also facilitated generation of the appendages of the affected skin, thus promoting restoration of the skin function. Our results provide a new possible therapy idea for the treatment of skin wounds with respect to both anatomical regeneration and functional restoration. PMID:27597871

  18. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin.

    PubMed

    Hanna, Jacob; Wernig, Marius; Markoulaki, Styliani; Sun, Chiao-Wang; Meissner, Alexander; Cassady, John P; Beard, Caroline; Brambrink, Tobias; Wu, Li-Chen; Townes, Tim M; Jaenisch, Rudolf

    2007-12-21

    It has recently been demonstrated that mouse and human fibroblasts can be reprogrammed into an embryonic stem cell-like state by introducing combinations of four transcription factors. However, the therapeutic potential of such induced pluripotent stem (iPS) cells remained undefined. By using a humanized sickle cell anemia mouse model, we show that mice can be rescued after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells. This was achieved after correction of the human sickle hemoglobin allele by gene-specific targeting. Our results provide proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy.

  19. Inhibition of tumour promotion in mouse skin by extracts of rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia), unique South African herbal teas.

    PubMed

    Marnewick, Jeanine; Joubert, Elizabeth; Joseph, Shamiel; Swanevelder, Sonja; Swart, Pieter; Gelderblom, Wentzel

    2005-06-28

    The modulating effect of ethanol/acetone (E/A) soluble fractions, prepared from methanolic extracts of processed and unprocessed rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia) as well as green (Camellia sinensis) teas was established in a two-stage mouse skin carcinogenesis assay. Topical application of the tea fractions prior to the tumour promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), on ICR mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) suppressed skin tumorigenesis significantly (P<0.001) with the green tea E/A fraction exhibiting a 100% inhibition, unprocessed honeybush 90%, processed honeybush 84.2%, processed rooibos 75% and unprocessed rooibos 60%. The green tea fraction, with the highest flavanol/proanthocyanidin content, also exhibited the highest protective activity (99%) against hepatic microsomal lipid peroxidation, and completely inhibited skin tumour formation. Differences in the flavanol/proanthocyanidin and flavonol/flavone composition and/or non polyphenolic constituents are likely to be important determinants in the inhibition of tumour promotion by the herbal tea E/A fractions in mouse skin.

  20. YAP Regulates the Expression of Hoxa1 and Hoxc13 in Mouse and Human Oral and Skin Epithelial Tissues

    PubMed Central

    Liu, Ming; Zhao, Shuangyun; Lin, Qingjie

    2015-01-01

    Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans. PMID:25691658

  1. YAP regulates the expression of Hoxa1 and Hoxc13 in mouse and human oral and skin epithelial tissues.

    PubMed

    Liu, Ming; Zhao, Shuangyun; Lin, Qingjie; Wang, Xiu-Ping

    2015-04-01

    Yes-associated protein (YAP) is a Hippo signaling transcriptional coactivator that plays pivotal roles in stem cell proliferation, organ size control, and tumor development. The downstream targets of YAP have been shown to be highly context dependent. In this study, we used the embryonic mouse tooth germ as a tool to search for the downstream targets of YAP in ectoderm-derived tissues. Yap deficiency in the dental epithelium resulted in a small tooth germ with reduced epithelial cell proliferation. We compared the gene expression profiles of embryonic day 14.5 (E14.5) Yap conditional knockout and YAP transgenic mouse tooth germs using transcriptome sequencing (RNA-Seq) and further confirmed the differentially expressed genes using real-time PCR and in situ hybridization. We found that YAP regulates the expression of Hoxa1 and Hoxc13 in oral and dental epithelial tissues as well as in the epidermis of skin during embryonic and adult stages. Sphere formation assay suggested that Hoxa1 and Hoxc13 are functionally involved in YAP-regulated epithelial progenitor cell proliferation, and chromatin immunoprecipitation (ChIP) assay implies that YAP may regulate Hoxa1 and Hoxc13 expression through TEAD transcription factors. These results provide mechanistic insights into abnormal YAP activities in mice and humans.

  2. IL-21 reduces immediate hypersensitivity reactions in mouse skin by suppressing mast cell activation or IgE production.

    PubMed

    Tamagawa-Mineoka, Risa; Kishida, Tsunao; Mazda, Osam; Katoh, Norito

    2011-07-01

    IL-21 regulates activation, proliferation, and differentiation of various immune cells. We have previously shown that exogenous IL-21 administration reduces allergic reactions in mouse models of anaphylaxis and allergic rhinitis. However, the effects of IL-21 in allergic cutaneous reactions remain unclear. In this study, we examined the effects of IL-21 in a mouse model of the IgE-mediated cutaneous immediate hypersensitivity reaction (IHR). We also investigated the mechanism of IL-21-induced regulation of allergic cutaneous reactions. Mice were sensitized by intraperitoneal ovalbumin (OVA) injection and challenged by injecting OVA intradermally into the ears, with intraperitoneal administration of recombinant murine (rm)IL-21 during the sensitization period or after completion of sensitization. After challenge, IL-21-untreated allergic mice developed biphasic responses characterized by early-phase and late-phase reactions. The biphasic reactions were significantly reduced by rmIL-21 treatment during sensitization or after completion of sensitization. Administration of rmIL-21 during sensitization reduced the cutaneous IHR by suppressing allergen-specific IgE production. In contrast, administration of rmIL-21 after completion of sensitization did not decrease serum levels of allergen-specific IgE, but significantly suppressed mast cell degranulation in skin. These results suggest that the regulatory effects of IL-21 on the cutaneous IHR involve suppression of allergen-specific IgE production or mast cell degranulation.

  3. Dynamic change of histone H2AX phosphorylation independent of ATM and DNA-PK in mouse skin in situ

    SciTech Connect

    Koike, Manabu Mashino, Minako; Sugasawa, Jun; Koike, Aki

    2007-11-30

    Histone H2AX undergoes phosphorylation on Ser 139 ({gamma}-H2AX) rapidly in response to DNA double-strand breaks induced by exogenous stimuli, such as ionizing radiation. However, the endogenous phosphorylation pattern and modifier of H2AX remain unclear. Here we show that H2AX is regulated physically at the level of phosphorylation at Ser139 during a hair cycle in the mouse skin. In anagen hair follicles, {gamma}-H2AX-positive cells were observed in the outer root sheath (ORS) and hair bulb in a cycling inferior region but not in a permanent superficial region. In telogen hair follicles, {gamma}-H2AX-positive cells were only detected around the germ cell cap. In contrast, following X-irradiation, {gamma}-H2AX was observed in various cell types including the ORS cells in the permanent superficial region. Furthermore, {gamma}-H2AX-positive cells were detected in the skin of mice lacking either ATM or DNA-PK, suggesting that these kinases are not essential for phosphorylation in vivo.

  4. Disruption of protein kinase Ceta results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis.

    PubMed

    Chida, Kazuhiro; Hara, Takeshi; Hirai, Takaaki; Konishi, Chieko; Nakamura, Kenji; Nakao, Kazuki; Aiba, Atsu; Katsuki, Motoya; Kuroki, Toshio

    2003-05-15

    We have generated a mouse strain lacking protein kinase C (PKC) eta to evaluate its significance in epithelial organization and tumor formation. The PKCeta-deficient mice exhibited increased susceptibility to tumor formation in two-stage skin carcinogenesis by single application of 7,12-dimethylbenz(a)anthracene (DMBA) for tumor initiation and repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) for tumor promotion. The tumor formation was not enhanced by DMBA or TPA treatment alone, suggesting that PKCeta suppresses tumor promotion. Epidermal hyperplasia induced by topical TPA treatment was prolonged in the mutant mice. The enhanced tumor formation may be closely associated with the prolonged hyperplasia induced by topical TPA treatment. In the mutant mice, after inflicting injury by punch biopsy, wound healing on the dorsal skin, particularly reepithelialization, was significantly delayed and impaired in structure. Impairment of epithelial regeneration in wound healing indicates a possibility that PKCeta plays a role in maintenance of epithelial architecture. Homeostasis in epithelial tissues mediated by PKCeta is important for tumor formation in vivo. We propose that PKCeta is involved in tumor formation modulated by regulation of proliferation and remodeling of epithelial cells in vivo.

  5. Intravital two-photon microscopy of host-pathogen interactions in a mouse model of Staphylococcus aureus skin abscess formation.

    PubMed

    Liese, Jan; Rooijakkers, Suzan H M; van Strijp, Jos A G; Novick, Richard P; Dustin, Michael L

    2013-06-01

    Staphylococcus (S.) aureus is a frequent cause of severe skin infections. The ability to control the infection is largely dependent on the rapid recruitment of neutrophils (PMN). To gain more insight into the dynamics of PMN migration and host-pathogen interactions in vivo, we used intravital two-photon (2-P) microscopy to visualize S. aureus skin infections in the mouse. Reporter S. aureus strains expressing fluorescent proteins were developed, which allowed for detection of the bacteria in vivo. By employing LysM-EGFP mice to visualize PMN, we observed the rapid appearance of PMN in the extravascular space of the dermis and their directed movement towards the focus of infection, which led to the delineation of an abscess within 1 day. Moreover, tracking of transferred labelled bone-marrow neutrophils showed that PMN localization to the site of infection is dependent on the presence of G-protein-coupled receptors on the PMN, whereas Interleukin-1 receptor was required on host cells other than PMN. Furthermore, the S. aureus complement inhibitor Ecb could block PMN accumulation at thesite of infection. Our results establish that 2-P microscopy is a powerful tool to investigate the orchestration of the immune cells, S. aureus location and gene expression in vivo on a single cell level.

  6. Changes in arachidonic acid metabolism in UV-irradiated hairless mouse skin

    SciTech Connect

    Ruzicka, T.; Walter, J.F.; Printz, M.P.

    1983-10-01

    This study was conducted to investigate the metabolism of arachidonic acid in the skin of hairless mice exposed to UVA, PUVA, UVB, and UVC irradiation. The main products of arachidonic acid in the epidermis were hydroxyeicosatetraenoic acid (HETE), PGE2, and PGD2. Dermis displayed a lower lipoxygenase activity (expressed as HETE production) than the epidermis and showed no detectable cyclooxygenase activity, i.e., no prostaglandin production. The main changes observed in UV-induced inflammatory reactions were as follows. 1. A 5-fold increase in dermal HETE production in PUVA-treated animals and a 29% reduction in epidermal HETE formation after UVC treatment. 2. A marked decrease of PGD2 and a marked increase of PGE2 formation due to alterations of PGH2 metabolism in the UVB-treated group; however, cyclooxygenase activity was unchanged. These changes in arachidonic acid metabolism in the skin may be of pathophysiologic importance in UV-induced inflammatory reaction.

  7. Studies on the mechanisms involved in multistage carcinogenesis in mouse skin

    SciTech Connect

    Slaga, T.J.; Fischer, S.M.; Weeks, C.E.; Klein-Szanto, A.J.P.; Reiners, J.

    1982-01-01

    Skin tumors can be effectively induced in mice by the repetitive application of a carcinogen. The relative order of sensitivity to complete carcinogenesis is Sencar > CD-1 > C57BL/6 greater than or equal to BALB/c greater than or equal to ICR/Ha Swiss > C3H. Skin tumors in mice can also be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a weak or noncarcinogenic tumor promoter (promotion phase) followed by repetitive treatment with a weak or noncarcinogenic tumor promoter (promotion phase). The relative order of sensitivity to initiation-promotion is Sencar > > CD-1 > ICR/Ha Swiss greater than or equal to Balb/c > C57BL/6 greater than or equal to C3H greater than or equal to DBA/2. The phorbol ester tumor promoters have been shown to have several cellular and biochemical effects on the skin. Of all the observed phorbol ester related effects on the skin, the induction of epidermal cell proliferation, polyamines, prostagladins, and dark basal keratinocytes as well as other embryonic conditions appear to correlate the best with promotion. Mezerein, a weak promoter, was found to induce many cellular and biochemical changes similar to 12-O-tetradecanoylphorbol-13 acetate (TPA), especially epidermal hyperplasia and polyamines; however, it was not a potent inducer of dark cells. Although C57BL/6 mice are relatively resistant to initiation-promotion by PAH initiation and phorbol ester promotion, they are fairly sensitive to complete carcinogenesis by PAH. This suggests that the C57BL/6 mice are resistant to phorbol ester tumor promotion. Preliminary experiments suggest that C57BL/6 and Sencar mice respond qualitatively but not quantitatively to a single treatment with TPA.

  8. Dye-enhanced multimodal confocal microscopy for noninvasive detection of skin cancers in mouse models

    NASA Astrophysics Data System (ADS)

    Park, Jesung; Mroz, Pawel; Hamblin, Michael R.; Yaroslavsky, Anna N.

    2010-03-01

    Skin cancer is the most common form of human cancer. Its early diagnosis and timely treatment is of paramount importance for dermatology and surgical oncology. In this study, we evaluate the use of reflectance and fluorescence confocal microscopy for detecting skin cancers in an in-vivo trial with B16F10 melanoma and SCCVII squamous cell carcinoma in mice. For the experiments, the mice are anesthetized, then the tumors are infiltrated with aqueous solution of methylene blue and imaged. Reflectance images are acquired at 658 nm. Fluorescence is excited at 658 nm and registered in the range between 690 and 710 nm. After imaging, the mice are sacrificed. The tumors are excised and processed for hematoxylin and eosin histopathology, which is compared to the optical images. The results of the study indicate that in-vivo reflectance images provide valuable information on vascularization of the tumor, whereas the fluorescence images mimic the structural features seen in histopathology. Simultaneous dye-enhanced reflectance and fluorescence confocal microscopy shows promise for the detection, demarcation, and noninvasive monitoring of skin cancer development.

  9. Ultrastructural demonstration of chemical modification of melanogenesis in hairless mouse skin

    SciTech Connect

    Nishimura, M.; Gellin, G.A.; Hoshino, S.; Epstein, J.H.; Epstein, W.L.; Fukuyama, K.

    1982-02-01

    We investigated chemical and physical modifications of the genetically determined ultrastructure of melanosomes. The flank skin of hairless mice was treated with ultraviolet energy (UV) shorter than 320 nm or with a combination of a photosensitizer and UV (PUVA treatment). All melanosomes in the induced melanocytes and those in resident melanocytes in the ear skin showed eumelanogenesis, although the degree of melanin deposition differed considerably according to the induction process. Eumelanogenesis was most advanced in the resident melanocytes while PUVA-induced melanocytes showed more immature premelanosomes. We then topically applied 4-tertiary butyl catechol on the skin. The depigmenting agent caused an appearance of pheomelanosomes. The alteration in melanogenesis was seen most distinctly in premelanosomes of the PUVA-induced cells. Altered ultrastructure was also observed in matured melanosomes; this change was most apparent in the resident melanocytes. These findings indicate that cells with eumelanogenesis may undergo pheomelanogenesis. The present study demonstrated effects of chemicals on genetically determined function of melanocytes by quantitative analysis of melanosome ultrastructure.

  10. Unexpected reduction of skin tumorigenesis on expression of cyclin-dependent kinase 6 in mouse epidermis.

    PubMed

    Wang, Xian; Sistrunk, Christopher; Rodriguez-Puebla, Marcelo L

    2011-01-01

    Cyclin-dependent kinases (CDKs) 4 and 6 are important regulators of the G(1) phase of the cell cycle, share 71% amino acid identity, and are expressed ubiquitously. As a result, it was assumed that each of these kinases plays a redundant role regulating normal and neoplastic proliferation. In previous reports, we have described the effects of CDK4 expression in transgenic mice, including the development of epidermal hyperplasia and increased malignant progression to squamous cell carcinoma. To study the role of CDK6 in epithelial growth and tumorigenesis, we generated transgenic mice carrying the CDK6 gene under the keratin 5 promoter (K5CDK6). Similar to K5CDK4 mice, epidermal proliferation increased substantially in K5CDK6 mice; however, no hyperplasia was observed. CDK6 overexpression also triggered keratinocyte apoptosis in interfollicular and follicular epidermis as a compensatory mechanism to override aberrant proliferation. Unexpectedly, CDK6 overexpression results in decreased skin tumor development compared with wild-type siblings. The inhibition in skin tumorigenesis was similar to that previously reported in K5-cyclin D3 mice. Furthermore, biochemical analysis of the K5CDK6 epidermis showed preferential complex formation between CDK6 and cyclin D3, suggesting that this particular complex plays an important role in tumor restraint. These studies provide in vivo evidence that CDK4 and CDK6 play a similar role as a mediator of keratinocyte proliferation but differ in apoptosis activation and skin tumor development.

  11. Protandim, a Fundamentally New Antioxidant Approach in Chemoprevention Using Mouse Two-Stage Skin Carcinogenesis as a Model

    PubMed Central

    Liu, Jianfeng; Gu, Xin; Robbins, Delira; Li, Guohong; Shi, Runhua; McCord, Joe M.; Zhao, Yunfeng

    2009-01-01

    Oxidative stress is an important contributor to cancer development. Consistent with that, antioxidant enzymes have been demonstrated to suppress tumorigenesis when being elevated both in vitro and in vivo, making induction of these enzymes a more potent approach for cancer prevention. Protandim, a well-defined combination of widely studied medicinal plants, has been shown to induce superoxide dismutase (SOD) and catalase activities and reduce superoxide generation and lipid peroxidation in healthy human subjects. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandim-containing basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-κB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention. PMID:19384424

  12. Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model.

    PubMed

    Liu, Jianfeng; Gu, Xin; Robbins, Delira; Li, Guohong; Shi, Runhua; McCord, Joe M; Zhao, Yunfeng

    2009-01-01

    Oxidative stress is an important contributor to cancer development. Consistent with that, antioxidant enzymes have been demonstrated to suppress tumorigenesis when being elevated both in vitro and in vivo, making induction of these enzymes a more potent approach for cancer prevention. Protandim, a well-defined combination of widely studied medicinal plants, has been shown to induce superoxide dismutase (SOD) and catalase activities and reduce superoxide generation and lipid peroxidation in healthy human subjects. To investigate whether Protandim can suppress tumor formation by a dietary approach, a two-stage mouse skin carcinogenesis study was performed. At the end of the study, the mice on a Protandim-containing basal diet had similar body weight compared with those on the basal diet, which indicated no overt toxicity by Protandim. After three weeks on the diets, there was a significant increase in the expression levels of SOD and catalase, in addition to the increases in SOD activities. Importantly, at the end of the carcinogenesis study, both skin tumor incidence and multiplicity were reduced in the mice on the Protandim diet by 33% and 57% respectively, compared with those on basal diet. Biochemical and histological studies revealed that the Protandim diet suppressed tumor promoter-induced oxidative stress (evidenced by reduction of protein carbonyl levels), cell proliferation (evidenced by reduction of skin hyperplasia and suppression of PKC/JNK/Jun pathway), and inflammation (evidenced by reduction of ICAM-1/VCAM-1 expression, NF-kappaB binding activity, and nuclear p65/p50 levels). Overall, induction of antioxidant enzymes by Protandim may serve as a practical and potent approach for cancer prevention.

  13. The regularity of sustained firing reveals two populations of slowly adapting touch receptors in mouse hairy skin.

    PubMed

    Wellnitz, Scott A; Lesniak, Daine R; Gerling, Gregory J; Lumpkin, Ellen A

    2010-06-01

    Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell-neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of SAI function in mutant mice has been hindered because previous studies did not distinguish SAI responses from slowly adapting type II (SAII) responses, which are thought to arise from different end organs, such as Ruffini endings. Thus we sought methods to discriminate these afferent types. We developed an epidermis-up ex vivo skin-nerve chamber to record action potentials from afferents while imaging Merkel cells in intact receptive fields. Using model-based cluster analysis, we found that two types of slowly adapting receptors were readily distinguished based on the regularity of touch-evoked firing patterns. We identified these clusters as SAI (coefficient of variation = 0.78 +/- 0.09) and SAII responses (0.21 +/- 0.09). The identity of SAI afferents was confirmed by recording from transgenic mice with green fluorescent protein-expressing Merkel cells. SAI receptive fields always contained fluorescent Merkel cells (n = 10), whereas SAII receptive fields lacked these cells (n = 5). Consistent with reports from other vertebrates, mouse SAI and SAII responses arise from afferents exhibiting similar conduction velocities, receptive field sizes, mechanical thresholds, and firing rates. These results demonstrate that mice, like other vertebrates, have two classes of slowly adapting light-touch receptors, identify a simple method to distinguish these populations, and extend the utility of skin-nerve recordings for genetic dissection of touch receptor mechanisms.

  14. SKHIN/Sprd, a new genetically defined inbred hairless mouse strain for UV-induced skin carcinogenesis studies

    PubMed Central

    Perez, Carlos; Parker-Thornburg, Jan; Mikulec, Carol; Kusewitt, Donna F.; Fischer, Susan M.; DiGiovanni, John; Conti, Claudio J.; Benavides, Fernando

    2013-01-01

    Strains of mice vary in their susceptibility to ultra-violet (UV) radiation-induced skin tumors. Some strains of hairless mice (homozygous for the spontaneous Hrhr mutation) are particularly susceptible to these tumors. The skin tumors that develop in hairless mice resemble, both at the morphologic and molecular levels, UV-induced squamous cell carcinomas (SCC) and their precursors in human. The most commonly employed hairless mice belong to the SKH1 stock. However, these mice are outbred and their genetic background is not characterized, which makes them a poor model for genetic studies. We have developed a new inbred strain from outbred SKH1 mice that we named SKHIN/Sprd (now at generation F31). In order to characterize the genetic background of this new strain, we genotyped a cohort of mice at F30 with 92 microsatellites and 140 single nucleotide polymorphisms (SNP) evenly distributed throughout the mouse genome. We also exposed SKHIN/Sprd mice to chronic UV irradiation and showed that they are as susceptible to UV-induced skin carcinogenesis as outbred SKH1 mice. In addition, we proved that, albeit with low efficiency, inbred SKHIN/Sprd mice are suitable for transgenic production by classical pronuclear microinjection. This new inbred strain will be useful for the development of transgenic and congenic strains on a hairless inbred background as well as the establishment of syngeneic tumor cell lines. These new tools can potentially help elucidate a number of features of the cutaneous response to UV irradiation in humans, including the effect of genetic background and modifier genes. PMID:22379968

  15. Resveratrol modulates phorbol ester-induced pro-inflammatory signal transduction pathways in mouse skin in vivo: NF-kappaB and AP-1 as prime targets.

    PubMed

    Kundu, Joydeb Kumar; Shin, Young Kee; Surh, Young-Joon

    2006-11-30

    Functional abnormalities of intracellular signaling network cause the disruption in homeostasis maintained by critical cellular components, thereby accelerating premalignant and malignant transformation. Multiple lines of evidence suggest that an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to tumorigenesis. The exposure to oxidative/pro-inflammatory stimuli turns on signaling arrays mediated by diverse classes of kinases and transcription factors, which may lead to aberrant expression of COX-2. We have attempted to unravel the signal transduction pathways involved in elevated COX-2 expression in mouse skin stimulated with a prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and its modulation by resveratrol, a phytoalexin known to exert potential chemopreventive effects. Our study revealed that topical application of TPA induced COX-2 expression in mouse skin via activation of nuclear factor-kappaB (NF-kappaB), which is regulated by upstream IkappaB kinase (IKK) or differentially by mitogen-activated protein (MAP) kinases. Besides NF-kappaB, the p38 MAP kinase-mediated activation of activator protein-1 (AP-1) has also been attributed to TPA-induced COX-2 expression in mouse skin. Among the MAP kinases, extracellular signal-regulated protein kinase (ERK) and p38 MAP kinase have been shown to regulate TPA-induced NF-kappaB activation, while p38 MAP kinase and c-Jun-N-terminal kinase are preferentially involved in TPA-induced activation of AP-1 in mouse skin in vivo. This commentary focuses on resveratrol modulation of intracellular signaling pathways involved in aberrant COX-2 expression in TPA-stimulated mouse skin to delineate molecular mechanisms underlying antitumor promoting effects of resveratrol.

  16. Tumorigenesis in athymic nude mouse skin by chemical carcinogens and ultraviolet light

    SciTech Connect

    Anderson, L.M.; Rice, J.M.

    1987-01-01

    A variety of established skin tumorigenesis protocols were tested for efficacy on athymic nu/nu mice (BALB/c background) and compared on euthymic nu/+ counterparts. Chemical carcinogens and UV light were applied to the ears of 10 mice of each sex and genotype for each group. Treatments were: 0.5 mg 7,12-dimethylbenz(a)anthracene ((DMBA) CAS: 57-97-6) to each ear; 0.125 mg DMBA to each ear, followed by 0.1 microgram 12-O-tetradecanoylphorbol-13-acetate ((TPA) CAS: 16561-29-8) twice weekly for 56 weeks; 0.2 mg N-nitroso-N-methylurea ((NMU) CAS: 684-93-5; 1% in acetone, 20 microliter) to each ear; 0.1 mg NMU to each ear weekly for 30 weeks; 0.2 mg NMU to each ear, followed by TPA twice weekly for 56 weeks; two ip doses of N-nitroso-N-ethylurea ((NEU) CAS: 759-73-9; 25 mg/kg each), followed by TPA twice weekly topically for 56 weeks; and exposure to sunlamps (250- to 400-nm emission) two or three times per week for 20 weeks, for a total dose of 3.7 X 10(5) J/m2. The chemical treatments caused mainly squamous papillomas and carcinomas, sebaceous adenomas and adenocarcinomas, and basal cell tumors, which appeared both on the skin of the ears and elsewhere. UV light caused squamous tumors, basal cell tumors, and sarcomas. Ear skin of the nu/nu mice developed significantly more squamous tumors than those of nu/+ mice after DMBA-TPA, NMU-TPA, NEU-TPA, repeated NMU, or UV light. Similar results were obtained for the skin of the heads and bodies. Even a single dose of NMU caused a few tumors on the nude, but not the euthymic, mice. A single dose of DMBA caused primarily sebaceous adenomas, distributed at random over the entire bodies. These results show that, contrary to previous reports, nude mice are sensitive to skin tumorigenesis, more so than euthymic nu/+ mice similarly exposed to diverse types of carcinogen and treatment protocols.

  17. Inhibition of akt enhances the chemopreventive effects of topical rapamycin in mouse skin

    USGS Publications Warehouse

    Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R.; Liu, Zhonglin; Barber, Christie; Rusche, Jadrian J.; Petricoin, Emmanuel; Calvert, Valerie; Einspahr, Janine G.; Dickinson, Jesse; Stratton, Steven P.; Curiel-Lewandrowski, Clara; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M.; Dong, Zigang; Alberts, David S.; Bowden, G. Timothy

    2016-01-01

    The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

  18. Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin.

    PubMed

    Dickinson, Sally E; Janda, Jaroslav; Criswell, Jane; Blohm-Mangone, Karen; Olson, Erik R; Liu, Zhonglin; Barber, Christy; Petricoin, Emanuel F; Calvert, Valerie S; Einspahr, Janine; Dickinson, Jesse E; Stratton, Steven P; Curiel-Lewandrowski, Clara; Saboda, Kathylynn; Hu, Chengcheng; Bode, Ann M; Dong, Zigang; Alberts, David S; Timothy Bowden, G

    2016-03-01

    The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.

  19. Targeted deletion of Crif1 in mouse epidermis impairs skin homeostasis and hair morphogenesis

    PubMed Central

    Shin, Jung-Min; Choi, Dae-Kyoung; Sohn, Kyung-Cheol; Kim, Ji-Young; Im, Myung; Lee, Young; Seo, Young-Joon; Shong, Minho; Lee, Jeung-Hoon; Kim, Chang Deok

    2017-01-01

    The epidermis, which consists mainly of keratinocytes, acts as a physical barrier to infections by regulating keratinocyte proliferation and differentiation. Hair follicles undergo continuous cycling to produce new one. Therefore, optimum supply of energy from the mitochondria is essential for maintaining skin homeostasis and hair growth. CRIF1 is a mitochondrial protein that regulates mitoribosome-mediated synthesis and insertion of mitochondrial oxidative phosphorylation polypeptides into the mitochondrial membrane in mammals. Recent studies reveal that conditional knockout (cKO) of Crif1 in specific tissues of mice induced mitochondrial dysfunction. To determine whether the mitochondrial function of keratinocytes affects skin homeostasis and hair morphogenesis, we generated epidermis-specific Crif1 cKO mice. Deletion of Crif1 in epidermis resulted in impaired mitochondrial function and Crif1 cKO mice died within a week. Keratinocyte proliferation and differentiation were markedly inhibited in Crif1 cKO mice. Furthermore, hair follicle morphogenesis of Crif1 cKO mice was disrupted by down-regulation of Wnt/β-catenin signaling. These results demonstrate that mitochondrial function in keratinocytes is essential for maintaining epidermal homeostasis and hair follicle morphogenesis. PMID:28317864

  20. In vivo imaging reveals a pioneer wave of monocyte recruitment into mouse skin wounds.

    PubMed

    Rodero, Mathieu P; Licata, Fabrice; Poupel, Lucie; Hamon, Pauline; Khosrotehrani, Kiarash; Combadiere, Christophe; Boissonnas, Alexandre

    2014-01-01

    The cells of the mononuclear phagocyte system are essential for the correct healing of adult skin wounds, but their specific functions remain ill-defined. The absence of granulation tissue immediately after skin injury makes it challenging to study the role of mononuclear phagocytes at the initiation of this inflammatory stage. To study their recruitment and migratory behavior within the wound bed, we developed a new model for real-time in vivo imaging of the wound, using transgenic mice that express green and cyan fluorescent proteins and specifically target monocytes. Within hours after the scalp injury, monocytes invaded the wound bed. The complete abrogation of this infiltration in monocyte-deficient CCR2(-/-) mice argues for the involvement of classical monocytes in this process. Monocyte infiltration unexpectedly occurred as early as neutrophil recruitment did and resulted from active release from the bloodstream toward the matrix through microhemorrhages rather than transendothelial migration. Monocytes randomly scouted around the wound bed, progressively slowed down, and stopped. Our approach identified and characterized a rapid and earlier than expected wave of monocyte infiltration and provides a novel framework for investigating the role of these cells during early stages of wound healing.

  1. Modulatory influence of chlorophyllin on the mouse skin papillomagenesis and xenobiotic detoxication system.

    PubMed

    Singh, A; Singh, S P; Bamezai, R

    1996-07-01

    The present study evaluates the modulatory potential of chlorophyllin (CHL) on the murine skin papillomagenesis pattern and its influence on the levels of biotransformation system enzymes. Topical application of CHL (100 mg/kg body weight/day) during peri-, post- or peri- and post-initiational stages of 7,12-dimethylbenz[a]anthracene (DMBA)-induced papillomagenesis, significantly (P < 0.01) reduced the (i) tumor burden to 3.68, 3.56 and 3.33 (positive control value: 5.89); (ii) cumulative number of papillomas to 59, 57 and 60 (positive control value: 112); and (iii) incidence of mice bearing papillomas to 88%, 88% and 90%, respectively (positive control value 100%). CHL treatment alone or during peri-, post-, or peri- and post-initiational stages significantly elevated the glutathione S-transferase (GST) and -SH levels in the liver and skin tissue of the murine system. The potential of CHL in modulating the process of carcinogenesis is suggested by the altered levels of biotransformation system enzymes. The implications of the biochemical changes and inhibition of tumor incidence by CHL are discussed.

  2. The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin.

    PubMed

    Chun, Kyung-Soo; Langenbach, Robert

    2011-06-01

    We previously reported that cycloogenase (COX)-2-generated prostaglandin E2 (PGE2) had anti-apoptotic effects in UVB-exposed mouse skin that involved EP2-mediated signaling (Chun et al., Cancer Res. 2007; 67: 2015). Because survivin is a regulator of cell survival, the possible involvement of COX-2 and EP2 in survivin expression following UVB exposure of mouse skin was investigated. In wild type mice, UVB exposure time-dependently increased the levels of survivin and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), a transcription factor that regulates survivin expression; and COX-2- or EP2-deficiency significantly reduced their induction. Topical application of the COX-2 inhibitor, celecoxib, also reduced UVB-induced survivin levels. To further investigate the roles of PGE2 and EP2 in the regulation of survivin, indomethacin was used to inhibit UVB-induced endogenous PG production. UVB-induced survivin levels were reduced by indomethacin, and PGE2 and the EP2 agonist, butaprost, partially restored survivin levels. The epidermal growth factor receptor (EGFR) is a downstream effector of EP2 and EGFR inhibition (AG1478) significantly reduced UVB activation of STAT3 and survivin levels. UVB-induced epidermal apoptosis in COX-2-/- mice was reduced by butaprost and EGFR inhibition blocked butaprost’s protective effects. Furthermore, butaprost in the absence of UVB exposure time-dependently increased p-EGFR, p-STAT3, and survivin levels in naïve mouse skin, whereas the EP4 agonist, PGE1 alcohol, did not significantly increase p-STAT3 or survivin levels. These data suggest that COX-2-generated PGE2 regulates survivin expression in mouse skin, in part, via an EP2-mediated EGFR/STAT3 pathway. Therefore, targeting the EP2/survivin pathway may provide a strategy for the chemoprevention/chemotherapy of skin cancer.

  3. A splice variant of alpha 6 integrin is associated with malignant conversion in mouse skin tumorigenesis.

    PubMed Central

    Tennenbaum, T; Belanger, A J; Glick, A B; Tamura, R; Quaranta, V; Yuspa, S H

    1995-01-01

    The epithelial-specific integrin alpha 6 beta 4 is suprabasally expressed in benign skin tumors (papillomas) and is diffusely expressed in carcinomas associated with an increase in the proliferating compartment. Analysis of RNA samples by reverse transcriptase-PCR and DNA sequencing revealed that chemically or oncogenically induced papillomas (n = 8) expressed a single transcript of the alpha 6 subunit, identified as the alpha 6 A splice variant. In contrast, carcinomas (n = 13) expressed both alpha 6A and an alternatively spliced form, alpha 6B. Primary keratinocytes and a number of keratinocyte cell lines that vary in biological potential from normal skin, to benign papillomas, to well-differentiated slowly growing carcinomas exclusively expressed alpha 6A. However, I7, an oncogene-induced cell line that produces highly invasive carcinomas, expressed both alpha 6A and alpha 6B transcript and protein. The expression of alpha 6B in I7 cells was associated with increased attachment to a laminin matrix compared to cell lines exclusively expressing alpha 6A. Furthermore, introduction of an alpha 6B expression vector into a papilloma cell line expressing alpha 6A increased laminin attachment. When a papilloma cell line was converted to an invasive carcinoma by introduction of the v-fos oncogene, the malignant cells expressed both alpha 6A and alpha 6B, while the parent cell line and cells transduced with v-jun or c-myc, which retained the papilloma phenotype, expressed only alpha 6A. Comparative analysis of alpha 6B expression in cell lines and their derived tumors indicate that alpha 6B transcripts are more abundant in tumors than cell lines, and alpha 6B is expressed to a greater extent in poorly differentiated tumors. These results establish a link between malignant conversion and invasion of squamous tumor cells and the regulation of transcript processing of the alpha 6 beta 4 integrin. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7624366

  4. Solar-UV-signature mutation prefers TCG to CCG: extrapolative consideration from UVA1-induced mutation spectra in mouse skin.

    PubMed

    Ikehata, Hironobu; Kumagai, Jun; Ono, Tetsuya; Morita, Akimichi

    2013-08-01

    UVA1 exerts its genotoxicity on mammalian skin by producing cyclobutane pyrimidine dimers (CPDs) in DNA and preferentially inducing solar-UV-signature mutations, C → T base substitution mutations at methylated CpG-associated dipyrimidine (Py-mCpG) sites, as demonstrated previously using a 364 nm laser as a UVA1 source and lacZ-transgenic mice that utilize the transgene as a mutational reporter. In the present study, we confirmed that a broadband UVA1 source induced the same mutation profiles in mouse epidermis as the UVA1 laser, generalizing the previous result from a single 364 nm to a wider wavelength range of UVA1 (340-400 nm). Combined with our previous data on the mutation spectra induced in mouse epidermis by UVB, UVA2 and solar UVR, we proved that the solar-UV-signature mutation is commonly observed in the wavelength range from UVB to UVA, and found that UVA1 induces this mutation more preferentially than the other shorter wavelength ranges. This finding indicates that the solar-UV-signature mutation-causing CPDs, which are known to prefer Py-mCpG sites, could be produced with the energy provided by the longer wavelength region of UVR, suggesting a photochemical reaction through the excitation of pyrimidine bases to energy states that can be accomplished by absorption of even low-energy UVR. On the other hand, the lower proportions of solar-UV-signature mutations observed in the mutation spectra for UVB and solar UVR indicate that the direct photochemical reaction through excited singlet state of pyrimidine bases, which can be accomplished only by high-energy UVR, is also involved in the mutation induction at those shorter wavelengths of UVR. We also found that the solar-UV signature prefers 5'-TCG-3' to 5'-CCG-3' as mutational target sites, consistent with the fact that UVA induces CPDs selectively at thymine-containing dipyrimidine sites and that solar UVR induces them preferably at Py-mCpG sites. However, the mutation spectrum in human p53 gene from non

  5. Protection against 12-O-tetradecanoylphorbol-13-acetate-caused inflammation in SENCAR mouse ear skin by polyphenolic fraction isolated from green tea.

    PubMed

    Katiyar, S K; Agarwal, R; Ekker, S; Wood, G S; Mukhtar, H

    1993-03-01

    Earlier studies conducted in our laboratory have shown that a polyphenolic fraction isolated from green tea (GTP) possesses anti-skin tumor initiating and anti-skin tumor promoting activity in the two-stage skin tumorigenesis protocol in SENCAR mouse. We have also shown that topical application of GTP inhibits tumor promoter-caused induction of epidermal ornithine decarboxylase activity in SENCAR mice in a dose-dependent manner, and that its oral feeding in drinking water to SKH-1 hairless mice enhances antioxidant and phase II enzyme activity in liver, lung, small bowel and skin. In this study, we show that single or multiple applications of GTP on SENCAR mouse ear prior to or after the application of 12-O-tetradecanoylphorbol-13-acetate (TPA) afford significant protection (P < 0.05) against TPA-induced edema. Pre-application of GTP also afforded significant protection against TPA-induced hyperplasia in the ear skin. The percentage protection by GTP both in terms of epidermal thickness and vertical cell layers was 75 and 90% respectively (P < 0.005). In further studies, we assessed the protective effect of GTP against TPA-caused infiltration of neutrophils in the ear skin of SENCAR mouse, by determining a naturally occurring constituent of neutrophils, myeloperoxidase, as a quantitative marker of tissue neutrophil content. Prior application of GTP resulted in significant protection against TPA-caused infiltration of neutrophils (P < 0.005). These results suggest that GTP possesses potential as a cancer chemopreventive agent against stage I tumor promotion.

  6. Effect of low molecular weight chitosans on drug permeation through mouse skin: 1. Transdermal delivery of baicalin.

    PubMed

    Zhou, Xueqin; Liu, Dongzhi; Liu, Haiyan; Yang, Qiaoli; Yao, Kangde; Wang, Xueyan; Wang, Lei; Yang, Xinjian

    2010-07-01

    The aim of this work was to evaluate the low molecular weight chitosans (LMWCs) as enhancers of transdermal administration of baicalin, an useful drug for the treatment of atopic dermatitis, viral hepatitis, and HIV infection. Permeation experiments were performed in vitro through mouse skin by using Franz cells. Improved baicalin skin penetration was obtained with the addition of LMWCs or D-glucosamine (beta-D-GlcNH(2)) to the donor solutions. Chitosan molecular weight, degree of deacetylation, pH of donor baicalin solutions, and enhancer concentration all affected LMWC enhancement effects. Significant enhancement was observed at pH 7.0 or 7.5 for CS80-1000, and the enhancement factor (EF) in the co-delivery method was calculated as 11.7 or 15.9, respectively. Simultaneously, beta-D-GlcNH(2) showed greatest enhancement at pH 7.0 with an EF of 11. Moreover, there was an optimal concentration range (0.5-1% by weight for CS80-1000 and 1.0-1.5% for beta-D-GlcNH(2)) to enhance baicalin transdermal delivery. It was concluded that the effective fractions for the enhancement of LMWCs were beta-D-GlcNH(2) oligomers, and the repeated number of beta-D-GlcNH(2) was suggested to be in the range 2-6. Enhancement mechanism of LMWCs was also discussed and suggested to be relative to the interactions of LMWC with both baicalin and the lipid of stratum corneum.

  7. Systemic morphine treatment induces changes in firing patterns and responses of nociceptive afferent fibers in mouse glabrous skin.

    PubMed

    Hogan, Dale; Baker, Alyssa L; Morón, Jose A; Carlton, Susan M

    2013-11-01

    Patients receiving opioids for pain may experience decreased effectiveness of the drug and even abnormal pain sensitivity-hyperalgesia and/or allodynia. We hypothesized that peripheral nociceptor hyperexcitability contributes to opioid-induced hyperalgesia and tested this using an in vitro mouse glabrous skin-nerve preparation. Mice were injected intraperitoneally with escalating doses of morphine (5, 8, 10, 15 mg/kg) or saline every 12 hours for 48 hours and killed approximately 12 hours after the last injection. Receptive fields of nociceptors were tested for mechanical, heat, and cold sensitivity. Activity was also measured during an initial 2-minute period and during 5-minute periods between stimuli. Aberrant activity was common in fibers from morphine-treated mice but rare in saline-treated mice. Resting background activity was elevated in C-fibers from morphine-treated mice. Both C- and Aδ-fibers had afterdischarge in response to mechanical, heat, and/or cold stimulation of the skin as well as spontaneous, unevoked activity. Compared to saline, morphine treatment increased the proportion of fibers displaying polymodal rather than mechanical-only responses. A significant increase in Aδ-mechanoreceptive fibers responding to cold accounted for most of this change. In agreement with this, morphine-treated mice showed increased sensitivity in the cold tail flick test. In morphine-treated mice, aberrant activity and hyperexcitability of nociceptors could contribute to increased pain sensitivity. Importantly, this activity is likely driving central sensitization, a phenomenon contributing to abnormal sensory processing and chronic pain. If similar changes occur in human patients, aberrant nociceptor activity is likely to be interpreted as pain and could contribute to opioid-induced hyperalgesia.

  8. Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models

    NASA Astrophysics Data System (ADS)

    Rollakanti, Kishore; Anand, Sanjay; Maytin, Edward V.

    2015-03-01

    Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6- fold in vivo. In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p <0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care.

  9. Comparison of the Transcriptomes of Mouse Skin Derived Precursors (SKPs) and SKP-Derived Fibroblasts (SFBs) by RNA-Seq

    PubMed Central

    Mao, Yujie; Xiong, Lidan; Wang, Siyu; Zhong, Jianqiao; Zhou, Rongying; Li, Li

    2015-01-01

    Skin-derived precursors (SKPs) from dermis possess the capacities of self-renewal and multipotency. In vitro and in vivo studies demonstrated that they can differentiate into fibroblasts. However, little is known about the molecular mechanism of the differentiation of SKPs into fibroblasts. Here we compare the transcriptomes of mouse SKPs and SKP-derived fibroblasts (SFBs) by RNA-Seq analysis, trying to find differences in gene expression between the two kinds of cells and then elucidate the candidate genes that may play important roles in the differentiation of SKPs into fibroblasts. A total of 1971 differentially expressed genes (DEGs) were identified by RNA-Seq, which provided abundant data for further analysis. Gene Ontology enrichment analysis revealed that genes related to cell differentiation, cell proliferation, protein binding, transporter activity and membrane were significantly enriched. The most significantly up-regulated genes Wnt4, Wisp2 and Tsp-1 and down-regulated genes Slitrk1, Klk6, Agtr2, Ivl, Msx1, IL15, Atp6v0d2, Kcne1l and Thbs4 may play important roles in the differentiation of SKPs into fibroblasts. KEGG analysis showed that DEGs were significantly enriched in the TGF-β signaling pathway, Wnt signaling pathway and Notch signaling pathway, which have been previously proven to regulate the differentiation and self-renewal of various stem cells. These identified DEGs and pathways could facilitate further investigations of the detailed molecular mechanisms, making it possible to take advantage of the potential therapeutic applications of SKPs in skin regeneration in the future. PMID:25719759

  10. Skin Vaccination against Cervical Cancer Associated Human Papillomavirus with a Novel Micro-Projection Array in a Mouse Model

    PubMed Central

    Corbett, Holly J.; Fernando, Germain J. P.; Chen, Xianfeng; Frazer, Ian H.; Kendall, Mark A. F.

    2010-01-01

    Background Better delivery systems are needed for routinely used vaccines, to improve vaccine uptake. Many vaccines contain alum or alum based adjuvants. Here we investigate a novel dry-coated densely-packed micro-projection array skin patch (Nanopatch™) as an alternate delivery system to intramuscular injection for delivering an alum adjuvanted human papillomavirus (HPV) vaccine (Gardasil®) commonly used as a prophylactic vaccine against cervical cancer. Methodology/Principal Findings Micro-projection arrays dry-coated with vaccine material (Gardasil®) delivered to C57BL/6 mouse ear skin released vaccine within 5 minutes. To assess vaccine immunogenicity, doses of corresponding to HPV-16 component of the vaccine between 0.43±0.084 ng and 300±120 ng (mean ± SD) were administered to mice at day 0 and day 14. A dose of 55±6.0 ng delivered intracutaneously by micro-projection array was sufficient to produce a maximal virus neutralizing serum antibody response at day 28 post vaccination. Neutralizing antibody titres were sustained out to 16 weeks post vaccination, and, for comparable doses of vaccine, somewhat higher titres were observed with intracutaneous patch delivery than with intramuscular delivery with the needle and syringe at this time point. Conclusions/Significance Use of dry micro-projection arrays (Nanopatch™) has the potential to overcome the need for a vaccine cold chain for common vaccines currently delivered by needle and syringe, and to reduce risk of needle-stick injury and vaccine avoidance due to the fear of the needle especially among children. PMID:20976136

  11. Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability change in mouse skin.

    PubMed

    Irie, K; Fujii, E; Ishida, H; Wada, K; Suganuma, T; Nishikori, T; Yoshioka, T; Muraki, T

    2001-05-01

    Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 microg site-1) from Salmonella typhimurium. Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg-1), milrinone (5 - 10 mg kg-1), rolipram (0.5 - 10 mg kg-1) and zaprinast (5 - 10 mg kg-1). The dye leakage was also inhibited by beta-adrenoceptor agonists, including isoproterenol (0.5 - 5 mg kg-1) and salbutamol (0.05 - 5 mg kg-1), an adenylate cyclase activator, forskolin (5 mg kg-1), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg-1). LPS caused a transient increase in serum TNF-alpha level peaking at 1 h after the injection. This increase in serum TNF-alpha was completely blocked by a pretreatment with pentoxifylline (160 mg kg-1), milrinone (5 mg kg-1), rolipram (1 mg kg-1), zaprinast (10 mg kg-1), salbutamol (0.5 mg kg-1), forskolin (1 mg kg-1) and 8-Br-cAMP (10 mg kg-1). LPS caused an increase in serum IL-1alpha level peaking at 3 h after injection. This increase in serum IL-1alpha was not significantly suppressed by the cyclic AMP elevating agents. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.

  12. Topical calcitriol prior to photodynamic therapy enhances treatment efficacy in non-melanoma skin cancer mouse models

    PubMed Central

    Rollakanti, Kishore; Anand, Sanjay; Maytin, Edward V.

    2015-01-01

    Non-melanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common form of human cancer worldwide, and their incidence is increasing. Photodynamic therapy (PDT), mediated by topically applied aminolevulinic acid (ALA) and subsequent exposure to light (either a laser or a noncoherent source), is being increasingly used for the treatment of dermatological disorders, including BCC and SCC. However, therapeutic responses of NMSCs to ALA-PDT are currently not superior to standard therapies, although the latter have undesirable side effects including scarring. In this study, we report that preconditioning of skin tumors with calcitriol (active form of Vitamin D; Vit D) prior to ALA-PDT, significantly improves the treatment outcome. In BCC and UVB-induced SCC mouse models, we identified an increase in tumor-specific accumulation of ALA induced photosensitizer (protoporphyrin IX, PpIX) due to Vit D preconditioning, of up to 6-fold in vivo. In addition, increased expression of differentiation (145 fold, p < 0.02) and proliferation (42 fold, p < 0.005) markers were identified in BCC tumors, all leading to increased tumor destruction (18.3 fold, p < 0.03) with the combination approach, as compared to ALA-PDT alone. Histomorphological changes identified using hematoxylin and eosin staining, and results of TUNEL staining, together documented a beneficial effect of Vit D pretreatment upon tumor cell death. We conclude that this new combination approach with Vit D and ALA-PDT has great potential to achieve complete remission of NMSC tumors, with excellent cosmetic results and an overall beneficial impact upon patient care. PMID:25983370

  13. Anti-Skin-Aging Effect of Epigallocatechin Gallate by Regulating Epidermal Growth Factor Receptor Pathway on Aging Mouse Model Induced by D-Galactose.

    PubMed

    Chen, Jiming; Li, Yifan; Zhu, Qiangqiang; Li, Tong; Lu, Hao; Wei, Nan; Huang, Yewei; Shi, Ruoyu; Ma, Xiao; Wang, Xuanjun; Sheng, Jun

    2017-03-23

    Epigallocatechin gallate(EGCG) is a monomer separated from tea catechins, as an well-known antioxidant, which helps fight wrinkles and rejuvenate skin cells. In this study, we investigated the anti-aging effect of EGCG, and to clarify underlying mechanism of skin aging in a D-galactose-induced aging mouse model. Forty-five male mice were divided into 5 groups and treated with different dose of EGCG, Vitamin C (VitC) to mice as a positive control. All groups except vehicle were established aging model induced by D-galactose (200mg/kg/day) that was subcutaneously injected to mice for 8 weeks. Two weeks after injection of D-galactose, EGCG and Vit C groups were simultaneously administered once a day by subcutaneously inject after 5hours for injecting D-galactose. The results show that EGCG can be absorbed by the skin. Overall, the conditions of the skin of EGCG-treatment groups were improved, the whole structure of skin were better than control groups, and the levels of oxidative stress and the expression of relate with EGFR proteins were significantly higher than control group after EGCG treatment. All these findings suggest that EGCG can resist skin senility effectively. And the EGFR with relate of downstream proteins are implicated in the skin aging.

  14. University of California San Francisco (UCSF-2): Gene Expression Profiling of Normal Mouse Skin, Hras WT and Hras -/- | Office of Cancer Genomics

    Cancer.gov

    University of California San Francisco (UCSF-2): Gene Expression Profiling of Normal Mouse Skin, Hras WT and Hras -/- This data set contains the transcriptional profiles of 20 dorsal skin samples from eight-week-old mice. Mice were generated by crossing FVB/N to Mus spretus mice to generate F1 mice, and then crossing F1 mice back to the FVB/N strain. 10  FVB/N mice lacking Hras1 (aka HrasKO, Hras-/-) and 10  FVB/N mice with wild-type Hras1 were generated. Read the abstract.

  15. Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome

    PubMed Central

    Yang, Annan; Currier, Duane; Poitras, Jennifer L.; Reeves, Roger H.

    2016-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra copy of human chromosome 21 (Hsa21). People with DS display multiple clinical traits as a result of the dosage imbalance of several hundred genes. While many outcomes of trisomy are deleterious, epidemiological studies have shown a significant risk reduction for most solid tumors in DS. Reduced tumor incidence has also been demonstrated in functional studies using trisomic DS mouse models. Therefore, it was interesting to find that Ts1Rhr trisomic mice developed more papillomas than did their euploid littermates in a DMBA-TPA chemical carcinogenesis paradigm. Papillomas in Ts1Rhr mice also proliferated faster. The increased proliferation was likely caused by a stronger response of trisomy to TPA induction. Treatment with TPA caused hyperkeratosis to a greater degree in Ts1Rhr mice than in euploid, reminiscent of hyperkeratosis seen in people with DS. Cultured trisomic keratinocytes also showed increased TPA-induced proliferation compared to euploid controls. These outcomes suggest that altered gene expression in trisomy could elevate a proliferation signalling pathway. Gene expression analysis of cultured keratinocytes revealed upregulation of several trisomic and disomic genes may contribute to this hyperproliferation. The contributions of these genes to hyper-proliferation were further validated in a siRNA knockdown experiment. The unexpected findings reported here add a new aspect to our understanding of tumorigenesis with clinical implications for DS and demonstrates the complexity of the tumor repression phenotype in this frequent condition. PMID:26752700

  16. Phenotypic changes and possible angiogenic roles of pericytes during wound healing in the mouse skin.

    PubMed

    Morikawa, Shunichi; Ezaki, Taichi

    2011-08-01

    Pericytes (PCs) are attracting increasing attention as a crucial target for anti-angiogenic therapy. In this study, we sought to determine the functional significance of PCs during angiogenesis by using a skin wound healing model in which different angiogenic stages are identifiable. Angiogenesis was first observed on Day 3 after wounding and increased greatly on Day 5. On Day 5, the leading edge of the regenerating vessels (vascular advancing front; VAF) appeared to be composed of immature vessels, and was further divided into "tip" and "following" regions according to maturational differences. PCs distributed in regenerating vessels showed phenotypic differences according to different regions. PCs that expressed PDGFR-β alone and lacked vascular basement membrane (BM) were predominant in the tip region of the VAF, while PCs that expressed both PDGFR-β and NG2 with their BM coating were numerous in the following regions toward the rear of the VAF. Moreover, PCs in the VAF expressed VEGF-A and associated with most proliferating endothelial cells (ECs). VEGF-A expression of PCs and the proliferating ECs totally disappeared in the region toward the rear of the VAF. We conclude that PCs can differ in their phenotype according to the stage of angiogenesis during wound healing. They may promote angiogenesis at the initial stage but might in turn stabilize the newly formed vessels at the later stage.

  17. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism.

    PubMed

    Onojafe, Ighovie F; Adams, David R; Simeonov, Dimitre R; Zhang, Jun; Chan, Chi-Chao; Bernardini, Isa M; Sergeev, Yuri V; Dolinska, Monika B; Alur, Ramakrishna P; Brilliant, Murray H; Gahl, William A; Brooks, Brian P

    2011-10-01

    Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.

  18. Topical tretinoin increases the tropoelastin and fibronectin content of photoaged hairless mouse skin.

    PubMed

    Schwartz, E; Kligman, L H

    1995-04-01

    Topical tretinoin treatment of photoaged hairless mice has been shown in previous studies to stimulate formation of a subepidermal zone of new connective tissue characterized by enhanced collagen synthesis. The aims of this study were to localize and/or quantify elastin, fibronectin, and glycosaminoglycans in the same model. Hairless mice (Skh-1) were irradiated thrice weekly for 10 weeks with gradually increasing doses of ultraviolet (up to 4.5 minimal erythema doses per exposure) from Westinghouse FS-40 bulbs. Mice were then treated five times a week with either 0.05% tretinoin, the ethanol:propylene glycol vehicle, or nothing for another 10 weeks. Controls included mice sacrificed after 10 weeks of ultraviolet treatment and age-matched untreated animals. The distribution of elastin and fibronectin was examined by immunofluorescence microscopy, which revealed fine fibrils in the subepidermal zone in tretinoin-treated skin. A quantitative slot-blot immunobinding assay showed that tretinoin induced a threefold higher amount of tropoelastin compared with controls. Insoluble elastin content (desmosine levels) was similar in all groups. Although fibronectin content was increased by ultraviolet radiation, tretinoin treatment induced the largest increase. In contrast, the amount of glycosaminoglycans, although increased by UVB radiation, was reduced by tretinoin treatment.

  19. Nonrandom duplication of the chromosome bearing a mutated Ha-ras-1 allele in mouse skin tumors.

    PubMed Central

    Bianchi, A B; Aldaz, C M; Conti, C J

    1990-01-01

    We analyzed the normal/mutated allelic ratio of the Ha-ras-1 gene in mouse skin squamous cell carcinomas induced by initiation with dimethylbenz[a]anthracene and promotion with phorbol 12-myristate 13-acetate. DNA for these studies was obtained from short-term tumor cultures (24-72 hr) to eliminate the contribution of stromal and inflammatory cells to the sample. The allelotypic analysis was performed in 25 squamous cell carcinomas by quantitative radio-analysis of the Xba I restriction fragment length polymorphism as detected by BS9, a v-Ha-ras probe, and rehybridization of the Southern blots with probes for chromosomes 7 and 8. Approximately 85% of the tumors presented overrepresentation of the mutated allele in the form of 1 normal/2 mutated (12 tumors), 0 normal/3 mutated (4 tumors), 0 normal/2 mutated (3 tumors), and gene amplification (3 tumors). No tumor was found with a 2 normal/1 mutated allelic ratio. These results support our previous cytogenetic studies, indicating that trisomy of chromosome 7 is present in the majority of these tumors and show that nonrandom duplication of the chromosome carrying the mutated Ha-ras-1 allele appears to be a major mechanism by which the mutated gene is overrepresented. Images PMID:1697691

  20. Spatially resolved bimodal spectroscopy for classification/evaluation of mouse skin inflammatory and pre-cancerous stages

    NASA Astrophysics Data System (ADS)

    Díaz-Ayil, Gilberto; Amouroux, Marine; Clanché, Fabien; Granjon, Yves; Blondel, Walter C. P. M.

    2009-07-01

    Spatially-resolved bimodal spectroscopy (multiple AutoFluorescence AF excitation and Diffuse Reflectance DR), was used in vivo to discriminate various healthy and precancerous skin stages in a pre-clinical model (UV-irradiated mouse): Compensatory Hyperplasia CH, Atypical Hyperplasia AH and Dysplasia D. A specific data preprocessing scheme was applied to intensity spectra (filtering, spectral correction and intensity normalization), and several sets of spectral characteristics were automatically extracted and selected based on their discrimination power, statistically tested for every pair-wise comparison of histological classes. Data reduction with Principal Components Analysis (PCA) was performed and 3 classification methods were implemented (k-NN, LDA and SVM), in order to compare diagnostic performance of each method. Diagnostic performance was studied and assessed in terms of Sensibility (Se) and Specificity (Sp) as a function of the selected features, of the combinations of 3 different inter-fibres distances and of the numbers of principal components, such that: Se and Sp ~ 100% when discriminating CH vs. others; Sp ~ 100% and Se > 95% when discriminating Healthy vs. AH or D; Sp ~ 74% and Se ~ 63% for AH vs. D.

  1. In vitro percutaneous absorption of tenoxicam from pressure-sensitive adhesive matrices across the hairless mouse skin.

    PubMed

    Gwak, H S; Chun, I K

    2001-12-01

    To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensitive adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PG)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) cosolvents with/without fatty acids. In this study, amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilizer. Among PSAs used, Duro-Tak 87-2510 showed much higher release rate than either Duro-Tak 87-2100 or Duro-Tak 87-2196. The relatively high flux rate was obtained with the formulation of DGME-PGML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose; the initial flux up to 12 h was 4.98 +/- 1.38 microg/cm2/h at the tenoxicam dose of 50 mg/70 cm2. This flux was much higher than that of a commercial piroxicam patch (Trast) (1.24 +/- 0.73 microg/ cm2/hr) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.

  2. Assessment of reinforced poly(ethylene glycol) chitosan hydrogels as dressings in a mouse skin wound defect model.

    PubMed

    Chen, Szu-Hsien; Tsao, Ching-Ting; Chang, Chih-Hao; Lai, Yi-Ting; Wu, Ming-Fung; Chuang, Ching-Nan; Chou, Hung-Chia; Wang, Chih-Kuang; Hsieh, Kuo-Haung

    2013-07-01

    Wound dressings of chitosan are biocompatible, biodegradable, antibacterial and hemostatic biomaterials. However, applications for chitosan are limited due to its poor mechanical properties. Here, we conducted an in vivo mouse angiogenesis study on reinforced poly(ethylene glycol) (PEG)-chitosan (RPC) hydrogels. RPC hydrogels were formed by cross-linking chitosan with PEGs of different molecular weights at various PEG to chitosan ratios in our previous paper. These dressings can keep the wound moist, had good gas exchange capacity, and was capable of absorbing or removing the wound exudate. We examined the ability of these RPC hydrogels and neat chitosan to heal small cuts and full-thickness skin defects on the backs of male Balb/c mice. Histological examination revealed that chitosan suppressed the infiltration of inflammatory cells and accelerated fibroblast proliferation, while PEG enhanced epithelial migration. The RPC hydrogels promoted wound healing in the small cuts and full layer wounds. The optimal RPC hydrogel had a swelling ratio of 100% and a water vapor transmission rate (WVTR) of about 2000 g/m(2)/day. In addition, they possess good mechanical property and appropriate degradation rates. Thus, the optimal RPC hydrogel formulation functioned effectively as a wound dressing and promoted wound healing.

  3. Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines.

    PubMed

    Olmeda, D; Montes, A; Moreno-Bueno, G; Flores, J M; Portillo, F; Cano, A

    2008-08-07

    Snai1 (Snail) and Snai2 (Slug), the two main members of Snail family factors, are important mediators of epithelial-mesenchymal transitions and involved in tumor progression. We recently reported that Snai1 plays a major role in tumor growth, invasion and metastasis, but the contribution of Snai2 to tumorigenesis is not yet well understood. To approach this question we have silenced Snai2 and/or Snai1 by stable RNA interference in two independent mouse skin carcinoma (HaCa4 and CarB) cell lines. We demonstrate that Snai2 knockdown has a milder effect, but collaborates with Snai1 silencing in reduction of tumor growth potential of either carcinoma cell line when injected into nude mice. Importantly, Snai1 or Snai2 silencing dramatically influences the metastatic ability of squamous carcinoma HaCa4 cells, inducing a strong reduction in liver and lung distant metastasis. However, only Snai1 knockdown has an effective action on invasiveness and fully abolishes tumor cell dissemination into the spleen. These results demonstrate that Snai1 and Snai2 collaborate on primary tumor growth and specifically contribute to site-specific metastasis of HaCa4 cells. These data also indicate that Snai1 is the major regulator of local invasion, supporting a hierarchical participation of both factors in the metastatic process.

  4. Humanized Mouse Model of Skin Inflammation Is Characterized by Disturbed Keratinocyte Differentiation and Influx of IL-17A Producing T Cells

    PubMed Central

    de Oliveira, Vivian L.; Keijsers, Romy R. M. C.; van de Kerkhof, Peter C. M.; Seyger, Marieke M. B.; Fasse, Esther; Svensson, Lars; Latta, Markus; Norsgaard, Hanne; Labuda, Tord; Hupkens, Pieter; van Erp, Piet E. J.; Joosten, Irma; Koenen, Hans J. P. M.

    2012-01-01

    Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response. As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human β-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our

  5. Chemomodulatory Effect of Trigonella foenum graecum (L.) Seed Extract on Two Stage Mouse Skin Carcinogenesis.

    PubMed

    Chatterjee, Sreemoyee; Kumar, Madhu; Kumar, Ashok

    2012-09-01

    Cancer is not a single disease but a group of complex genetic diseases of aged cells. Chemoprevention of cancer is the attempt to use natural and synthetic compounds to intervene in the early stages of cancer, before invasive disease begins. Consuming a diet rich in plant foods can provide a milieu of phytochemicals and non-nutritive plant substances that possess health-protective effects. Some phytochemicals derived in spices and herbs as well as other plants possess substantial cancer preventive properties. Thus the cancer chemo preventive potential of naturally occurring phytochemicals is of great interest because of their preventive role and as they are not perceived as "medicine". During the course of present study Trigonella foenum graecum (L.) seed- TFGS (commonly called fenugreek) extract was given at pre-initiational, post-initiational, promotional and throughout the experiment along with 7,12-dimethylbenz [a] anthracene DMBA and 12-O-tetradecanoylphorbol-13-acetate TPA treatment in Swiss albino mice. A significant reduction of papillomas in DMBA + TPA + TFGS (400 mg/kg. body wt.) treated group was found to be effective in decreasing the rate of tumor incidence in comparison to control. Furthermore, cumulative number of papillomas, tumor yield and tumor burden were also found to be reduced. The TFGS extract treatment before DMBA and TPA application (i.e. Pre initiation) were more effective than that of treatment during, and /or after DMBA treatment, however TFGS extract treatment was most effective when treated throughout all the stages of tumorigenesis. The TFGS treatment also showed a modulatory influence on mouse hepatic antioxidant defense system (GSH and LPO level).

  6. Epidermal hyperplasia in mouse skin following treatment with alternative drinking water disinfectants.

    PubMed

    Robinson, M; Bull, R J; Schamer, M; Long, R E

    1986-11-01

    Female SENCAR mice were treated with aqueous solutions of hypochlorous acid (HOCl), sodium hypochlorite (NaOCl), chlorine dioxide (ClO2), and monochloramine (NH2Cl) by whole body exposure (except head) for a 10-min period for 4 days in the first experiment and for 1 day (except NH2Cl) in the second experiment. Animals were sacrificed the day following the last treatment (experiment 1) or on day 1, 2, 3, 4, 5, 8, 10, and 12 following treatment (experiment 2), and skin thickness was measured by light microscopy at X400 by use of an eyepiece micrometer. Concentrations of disinfectants were 1, 10, 100, 300, and 1000 mg/L, for experiment 1 and 1000 mg/L for experiment 2. Thickness of the interfollicular epidermis (IFE) for control animals was 15.4 +/- 1.5 micron. After 4 days of treatment at 1000 mg/L, HOCl and ClO2 increased thickness to 39 +/- 7.0 and 40.2 +/- 11.8, and NaOCl increased thickness to 25.2 +/- 6.1 micron. Only HOCl and ClO2 were tested at 300 mg/L, yielding an IFE thickness of 30.0 +/- 13.1 and 16.8 +/- 0.8 micron, respectively. The response to HOCl was found to be dose-related; the minimally effective dose was 100 mg/L. In earlier, preliminary tests to determine optimum treatment schedule, the response to HOCl appeared to be maximal after 4 days of treatment and tended to decrease with further treatment. The time-course study following a single treatment of 1000 mg/L HOCl, however, showed a progression of IFE thickening of from 18.3 +/- 1.4 at 1 day to 30.8 +/- 8.0 at 8 days, decreasing to 19.1 +/- 6.2 micron at 12 days.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog

    SciTech Connect

    Boulware, Stephen; Fields, Tammy; McIvor, Elizabeth; Powell, K. Leslie; Abel, Erika L.; Vasquez, Karen M.; MacLeod, Michael C.

    2012-09-01

    Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (γ-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1 h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM. -- Highlights: ► 200 mM 2-(chloroethyl) ethyl sulfide (CEES) induces mutations in mouse skin. ► This dose of CEES is not overtly toxic, as assayed by histopathology. ► 2,6-Dithiopurine (DTP), applied after CEES-treatment, abolishes CEES-mutagenesis. ► This supports the idea that sulfur mustards exhibit long biological half-lives.

  8. 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog.

    PubMed

    Boulware, Stephen; Fields, Tammy; McIvor, Elizabeth; Powell, K Leslie; Abel, Erika L; Vasquez, Karen M; MacLeod, Michael C

    2012-09-01

    Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (γ-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM.

  9. Epidermal hyperplasia in mouse skin following treatment with alternative drinking water disinfectants.

    PubMed Central

    Robinson, M; Bull, R J; Schamer, M; Long, R E

    1986-01-01

    Female SENCAR mice were treated with aqueous solutions of hypochlorous acid (HOCl), sodium hypochlorite (NaOCl), chlorine dioxide (ClO2), and monochloramine (NH2Cl) by whole body exposure (except head) for a 10-min period for 4 days in the first experiment and for 1 day (except NH2Cl) in the second experiment. Animals were sacrificed the day following the last treatment (experiment 1) or on day 1, 2, 3, 4, 5, 8, 10, and 12 following treatment (experiment 2), and skin thickness was measured by light microscopy at X400 by use of an eyepiece micrometer. Concentrations of disinfectants were 1, 10, 100, 300, and 1000 mg/L, for experiment 1 and 1000 mg/L for experiment 2. Thickness of the interfollicular epidermis (IFE) for control animals was 15.4 +/- 1.5 micron. After 4 days of treatment at 1000 mg/L, HOCl and ClO2 increased thickness to 39 +/- 7.0 and 40.2 +/- 11.8, and NaOCl increased thickness to 25.2 +/- 6.1 micron. Only HOCl and ClO2 were tested at 300 mg/L, yielding an IFE thickness of 30.0 +/- 13.1 and 16.8 +/- 0.8 micron, respectively. The response to HOCl was found to be dose-related; the minimally effective dose was 100 mg/L. In earlier, preliminary tests to determine optimum treatment schedule, the response to HOCl appeared to be maximal after 4 days of treatment and tended to decrease with further treatment. The time-course study following a single treatment of 1000 mg/L HOCl, however, showed a progression of IFE thickening of from 18.3 +/- 1.4 at 1 day to 30.8 +/- 8.0 at 8 days, decreasing to 19.1 +/- 6.2 micron at 12 days.(ABSTRACT TRUNCATED AT 250 WORDS) Images FIGURE 3. A FIGURE 3. B FIGURE 3. C FIGURE 3. D FIGURE 3. E PMID:3028769

  10. Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing.

    PubMed

    Bonnart, Chrystelle; Deraison, Céline; Lacroix, Matthieu; Uchida, Yoshikazu; Besson, Céline; Robin, Aurélie; Briot, Anaïs; Gonthier, Marie; Lamant, Laurence; Dubus, Pierre; Monsarrat, Bernard; Hovnanian, Alain

    2010-03-01

    The human epidermis serves 2 crucial barrier functions: it protects against water loss and prevents penetration of infectious agents and allergens. The physiology of the epidermis is maintained by a balance of protease and antiprotease activities, as illustrated by the rare genetic skin disease Netherton syndrome (NS), in which impaired inhibition of serine proteases causes severe skin erythema and scaling. Here, utilizing mass spectrometry, we have identified elastase 2 (ELA2), which we believe to be a new epidermal protease that is specifically expressed in the most differentiated layer of living human and mouse epidermis. ELA2 localized to keratohyalin granules, where it was found to directly participate in (pro-)filaggrin processing. Consistent with the observation that ELA2 was hyperactive in skin from NS patients, transgenic mice overexpressing ELA2 in the granular layer of the epidermis displayed abnormal (pro-)filaggrin processing and impaired lipid lamellae structure, which are both observed in NS patients. These anomalies led to dehydration, implicating ELA2 in the skin barrier defect seen in NS patients. Thus, our work identifies ELA2 as a major new epidermal protease involved in essential pathways for skin barrier function. These results highlight the importance of the control of epidermal protease activity in skin homeostasis and designate ELA2 as a major protease driving the pathogenesis of NS.

  11. Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse. (I) Development of a model for screening studies in skin decontamination and protection.

    PubMed

    Dorandeu, F; Taysse, L; Boudry, I; Foquin, A; Hérodin, F; Mathieu, J; Daulon, S; Cruz, C; Lallement, G

    2011-06-01

    Exposure to lethal chemical warfare agents (CWAs) is no longer only a military issue due to the terrorist threat. Among the CWAs of concern are the organophosphorus nerve agent O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX) and the vesicant sulfur mustard (SM). Although efficient means of decontamination are available, most of them lose their efficacy when decontamination is delayed after exposure of the bare skin. Alternatively, CWA skin penetration can be prevented by topical skin protectants. Active research in skin protection and decontamination is thus paramount. In vivo screening of decontaminants or skin protectants is usually time consuming and may be expensive depending on the animal species used. We were thus looking for a suitable, scientifically sound and cost-effective model, which is easy to handle. The euthymic hairless mouse Crl: SKH-1 (hr/hr) BR is widely used in some skin studies and has previously been described to be suitable for some experiments involving SM or SM analogs. To evaluate the response of this species, we studied the consequences of exposing male anaesthetized SKH-1 mice to either liquid VX or to SM, the latter being used in liquid form or as saturated vapours. Long-term effects of SM burn were also evaluated. The model was then used in the companion paper (Taysse et al.(1)).

  12. Some lupane-type triterpenes inhibit tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin.

    PubMed

    Yasukawa, K; Yu, S; Yamanouchi, S; Takido, M; Akihisa, T; Tamura, T

    1995-04-01

    We have found that several lupane-type triterpenes, including lupeol, its acetate, betulin and betulinic acid, inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation, and that betulinic acid inhibits tumor promotion in two-stage carcinogenesis in mice. Among seven lupane-type triterpenes assayed, these compounds inhibited the inflammatory activity induced by TPA in mice. The 50 % inhibitory dose of these compounds for TPA-induced inflammation was 0.4-4.0 μmol. Furthermore, topical application of lupeol, lupeol 3-acetate and betulin markedly suppressed the tumor-promoting effect of TPA (1 μg/mouse) in mouse skin initiated with 7,12-dimethyl-benz[a]anthracene (50 μg/mouse), at a grade corresponding to that of betulinic acid.

  13. Topical gene silencing by iontophoretic delivery of an antisense oligonucleotide-dendrimer nanocomplex: the proof of concept in a skin cancer mouse model

    NASA Astrophysics Data System (ADS)

    Venuganti, , Venkata Vamsi K.; Saraswathy, Manju; Dwivedi, Chandradhar; Kaushik, Radhey S.; Perumal, Omathanu P.

    2015-02-01

    The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex reduced the tumor volume by 45% and was consistent with the reduction in Bcl-2 protein levels. The iontophoretically delivered ASO-dendrimer complex caused significant apoptosis in skin tumor. Overall, the findings from this study demonstrate that dendrimers are promising nanocarriers for developing topical gene silencing approaches for skin diseases.The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex

  14. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8⁺ T-cell accumulation in the skin.

    PubMed

    Harris, John E; Harris, Tajie H; Weninger, Wolfgang; Wherry, E John; Hunter, Christopher A; Turka, Laurence A

    2012-07-01

    Vitiligo is an autoimmune disease of the skin causing disfiguring patchy depigmentation of the epidermis and, less commonly, hair. Therapeutic options for vitiligo are limited, reflecting in part limited knowledge of disease pathogenesis. Existing mouse models of vitiligo consist of hair depigmentation but lack prominent epidermal involvement, which is the hallmark of human disease. They are thus unable to provide a platform to fully investigate disease mechanisms and treatment. CD8(+) T cells have been implicated in the pathogenesis of vitiligo, and expression of IFN-γ is increased in the lesional skin of patients, however, it is currently unknown what role IFN-γ has in disease. Here, we have developed an adoptive transfer mouse model of vitiligo using melanocyte-specific CD8(+) T cells, which recapitulates the human condition by inducing epidermal depigmentation while sparing the hair. Like active lesions in human vitiligo, histology of depigmenting skin reveals a patchy mononuclear infiltrate and single-cell infiltration of the epidermis. Depigmentation is accompanied by accumulation of autoreactive CD8(+) T cells in the skin, quantifiable loss of tyrosinase transcript, and local IFN-γ production. Neutralization of IFN-γ with antibody prevents CD8(+) T-cell accumulation and depigmentation, suggesting a therapeutic potential for this approach.

  15. Increased susceptibility to Staphylococcus aureus colonization of the skin of the NOA mouse: a potentially useful animal model for evaluating antiseptic effects.

    PubMed

    Kondo, Taizo; Ohno, Hitoshi; Taguchi, Keisuke; Satode, Ryotaro; Kondo, Toshio; Shiomoto, Yasuhisa

    2006-01-01

    Isolation of bacteria from wet skin lesions was attempted using Naruto Research Institute Otsuka Atrichia (NOA) mice, which develop such lesions spontaneously at a high rate. As a result, Staphylococcus aureus was demonstrated to have colonized the wet skin lesions at high density. In addition, the isolated S. aureus was found to be similar to the strain of S. aureus thought to colonize the eczematous lesions seen in humans with atopic dermatitis. Furthermore, a survey of the S. aureus colonization status of NOA mice with no wet skin lesions confirmed colonization at higher density than in HR-1 mice as control, indicating that the skin of the NOA mouse has the novel characteristic of increased susceptibility to S. aureus colonization. Thus, by using changes in S. aureus counts as an index, the NOA mouse can be expected to serve as a useful animal model for evaluating the effects of topical antiseptics. The antiseptic effects of an ointment and a lotion containing chlorhexidine gluconate were confirmed using this animal model.

  16. Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin.

    PubMed

    Ansari, Kausar M; Sung, You Me; He, Guobin; Fischer, Susan M

    2007-10-01

    The EP2 prostanoid receptor is one of the four subtypes of receptors for prostaglandin E2 (PGE2). We previously reported that deletion of EP2 led to resistance to chemically induced mouse skin carcinogenesis, whereas overexpression of EP2 resulted in enhanced tumor development. The purpose of this study was to investigate the underlying molecular mechanisms. We found that EP2 knockout mice had reduced cyclooxygenase-2 (COX-2) expression after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment compared with wild-type (WT) mice. Further, primary keratinocytes from EP2 transgenic mice had increased COX-2 expression after either TPA or PGE2 treatment and COX-2 expression was blocked by 10 microM SQ 22,536, an adenylate cyclase inhibitor. EP2 knockout mice had significantly decreased, whereas EP2 transgenic mice had significantly increased PGE2 production in response to a single treatment of TPA. Cyclic AMP response element-binding protein (CREB) phosphorylation was elevated to a greater extent in keratinocytes from EP2 transgenic mice compared with those of WT mice following PGE2 treatment. A protein kinase A (PKA) inhibitor reduced PGE2-mediated CREB phosphorylation in keratinocytes from EP2 transgenic mice. Furthermore, we found that there was no CREB phosphorylation in EP2 knockout mice following PGE2 treatment. PGE2-induced DNA synthesis (cell proliferation) was significantly decreased in keratinocytes from EP2 knockout mice following pretreatment with 10 microM SQ 22,536. Taken together, EP2 activation of the PKA/CREB-signaling pathway is responsible for keratinocyte proliferation and our findings reveal a positive feedback loop between COX-2 and PGE2 that is mediated by the EP2 receptor.

  17. Evaluation of the dermal carcinogenicity of lubricant base oils by the mouse skin painting bioassay and other proposed methods.

    PubMed

    Chasey, K L; McKee, R H

    1993-01-01

    Lubricant base oils are petroleum products that are predominantly derived from the vacuum distillation of crude oil. Various types of refinement can be employed during the manufacturing process, and evidence suggests that certain of the associated process streams produce skin cancer. Polycyclic aromatic compounds (PACs), some of which are considered as the causative agents, are removed, concentrated or chemically converted during the refinement process. In order to understand the effects of various types of refinement processes on carcinogenic potential, 94 oils were evaluated in the mouse epidermal cancer bioassay. This Exxon database is unique, because of the wide range of crude oils and processing histories represented. Seven processing history classifications are described, and conclusions concerning the impacts of each refinement process on dermal carcinogenicity are discussed. This research also included an evaluation of selected biological and chemical test methods for predicting carcinogenic potential. These included a modified version of the Ames test for mutagenicity, as well as analytical characterizations of the polycyclic aromatic structures in the oils. For classification purposes, a sample was considered to be carcinogenic if it resulted in the production of two or more tumor-bearing animals (in test groups of either 40 or 50 animals). The modified Ames test was considered to be positive if the mutagenicity index was > or = 2.0, and PAC analyses were similarly designated as positive or negative according to proposed guidelines. All of the alternative test methods showed similar agreement with dermal carcinogenicity bioassay data; concordance values were > or = 80%. However, each test was incorrect in ca. 10%-20% of the cases evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

  18. Characterization of the mechanisms underlying the inflammatory response to Polistes lanio lanio (paper wasp) venom in mouse dorsal skin.

    PubMed

    Yshii, Lídia M; Souza, Gustavo H M F; Camargo, Enilton A; Eberlin, Marcos N; Ribela, Maria Teresa C P; Muscará, Marcelo N; Hyslop, Stephen; Costa, Soraia K P

    2009-01-01

    Stings by Polistes wasps can cause life-threatening allergic reactions, pain and inflammation. We examined the changes in microvascular permeability and neutrophil influx caused by the venom of Polistes lanio a paper wasp found in southeastern Brazil. The intradermal injection of wasp venom caused long-lasting paw oedema and dose-dependently increased microvascular permeability in mouse dorsal skin. SR140333, an NK(1) receptor antagonist, markedly inhibited the response, but the NK(2) receptor antagonist SR48968 was ineffective. The oedema was reduced in capsaicin-treated rats, indicating a direct activation of sensory fibres. Dialysis of the venom partially reduced the oedema and the remaining response was further inhibited by SR140333. Mass spectrometric analysis of the venom revealed two peptides (QPPTPPEHRFPGLM and ASEPTALGLPRIFPGLM) with sequence similarities to the C-terminal region of tachykinin-like peptides found in Phoneutria nigriventer spider venom and vertebrates. Wasp venom failed to release histamine from mast cells in vitro and spectrofluorometric assay of the venom revealed a negligible content of histamine in the usual dose of P. l. lanio venom (1nmol of histamine/7mug of venom) that was removed by dialysis. The histamine H(1) receptor antagonist pyrilamine, but not bradykinin B(1) or B(2) receptor antagonists, inhibited venom-induced oedema. In conclusion, P. l. lanio venom induces potent oedema and increases vascular permeability in mice, primarily through activation of tachykinin NK(1) receptors by substance P released from sensory C fibres, which in turn releases histamine from dermal mast cells. This is the first description of a neurovascular mechanism for P. l. lanio venom-mediated inflammation. The extent to which the two tachykinin-like peptides identified here contribute to this neurogenic inflammatory response remains to be elucidated.

  19. Activation-induced cytidine deaminase is dispensable for virus-mediated liver and skin tumor development in mouse models.

    PubMed

    Nguyen, Tung; Xu, Jianliang; Chikuma, Shunsuke; Hiai, Hiroshi; Kinoshita, Kazuo; Moriya, Kyoji; Koike, Kazuhiko; Marcuzzi, Gian Paolo; Pfister, Herbert; Honjo, Tasuku; Kobayashi, Maki

    2014-07-01

    Activation-induced cytidine deaminase (AID) not only promotes immune diversity by initiating somatic hypermutation and class switch recombination in immunoglobulin genes but also provokes genomic instability by introducing translocations and mutations into non-immunoglobulin genes. To test whether AID is essential for virus-induced tumor development, we used two transgenic tumor models: mice expressing hepatitis C virus (HCV) core proteins (HCV-Tg), driven by the hepatitis B virus promoter, and mice expressing human papillomavirus type 8 proteins (HPV8-Tg), driven by the Keratin 14 promoter. Both strains were analyzed in the absence and presence of AID by crossing each with AID (-/-) mice. There was no difference in the liver tumor frequency between the HCV-Tg/AID (+/+) and HCV-Tg/AID (-/-) mice at 20 months of age although the AID (+/+) mice showed more severe histological findings and increased cytokine expression. Furthermore, a low level of AID transcript was detected in the HCV-Tg/AID (+/+) liver tissue that was not derived from hepatocytes themselves but from intra-hepatic immune cells. Although AID may not be the direct cause of HCV-induced oncogenesis, AID expressed in B cells, not in hepatocytes, may prolong steatosis and cause increased lymphocyte infiltration into HCV core protein-induced liver lesions. Similarly, there was no difference in the time course of skin tumor development between the HPV8-Tg/AID (-/-) and HPV8-Tg/AID (+/+) groups. In conclusion, AID does not appear to be required for tumor development in the two virus-induced tumor mouse models tested although AID expressed in infiltrating B cells may promote inflammatory reactions in HCV core protein-induced liver pathogenesis.

  20. Regulation of p53, nuclear factor {kappa}B and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin

    SciTech Connect

    Kalra, Neetu; Bhui, Kulpreet; Roy, Preeti; Srivastava, Smita; George, Jasmine; Prasad, Sahdeo; Shukla, Yogeshwer

    2008-01-01

    Bromelain is a pharmacologically active compound, present in stems and immature fruits of pineapples (Ananas cosmosus), which has been shown to have anti-edematous, anti-inflammatory, anti-thrombotic and anti-metastatic properties. In the present study, antitumorigenic activity of bromelain was recorded in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted 2-stage mouse skin model. Results showed that bromelain application delayed the onset of tumorigenesis and reduced the cumulative number of tumors, tumor volume and the average number of tumors/mouse. To establish a cause and effect relationship, we targeted the proteins involved in the cell death pathway. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in antiapoptotic protein Bcl-2 in mouse skin. Since persistent induction of cyclooxygenase-2 (Cox-2) is frequently implicated in tumorigenesis and is regulated by nuclear factor-kappa B (NF-{kappa}B), we also investigated the effect of bromelain on Cox-2 and NF-{kappa}B expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-{kappa}B by blocking phosphorylation and subsequent degradation of I{kappa}B{alpha}. In addition, bromelain treatment attenuated DMBA-TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), mitogen-activated protein kinase (MAPK) and Akt. Taken together, we conclude that bromelain induces apoptosis-related proteins along with inhibition of NF-{kappa}B-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced mouse skin tumors, which may account for its anti-tumorigenic effects.

  1. Regulation of p53, nuclear factor kappaB and cyclooxygenase-2 expression by bromelain through targeting mitogen-activated protein kinase pathway in mouse skin.

    PubMed

    Kalra, Neetu; Bhui, Kulpreet; Roy, Preeti; Srivastava, Smita; George, Jasmine; Prasad, Sahdeo; Shukla, Yogeshwer

    2008-01-01

    Bromelain is a pharmacologically active compound, present in stems and immature fruits of pineapples (Ananas cosmosus), which has been shown to have anti-edematous, anti-inflammatory, anti-thrombotic and anti-metastatic properties. In the present study, antitumorigenic activity of bromelain was recorded in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted 2-stage mouse skin model. Results showed that bromelain application delayed the onset of tumorigenesis and reduced the cumulative number of tumors, tumor volume and the average number of tumors/mouse. To establish a cause and effect relationship, we targeted the proteins involved in the cell death pathway. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in antiapoptotic protein Bcl-2 in mouse skin. Since persistent induction of cyclooxygenase-2 (Cox-2) is frequently implicated in tumorigenesis and is regulated by nuclear factor-kappa B (NF-kappaB), we also investigated the effect of bromelain on Cox-2 and NF-kappaB expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. In addition, bromelain treatment attenuated DMBA-TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK1/2), mitogen-activated protein kinase (MAPK) and Akt. Taken together, we conclude that bromelain induces apoptosis-related proteins along with inhibition of NF-kappaB-driven Cox-2 expression by blocking the MAPK and Akt/protein kinase B signaling in DMBA-TPA-induced mouse skin tumors, which may account for its anti-tumorigenic effects.

  2. Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development.

    PubMed

    Moulson, Casey L; Martin, Daniel R; Lugus, Jesse J; Schaffer, Jean E; Lind, Anne C; Miner, Jeffrey H

    2003-04-29

    Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.

  3. Development of dry skin in the NOA mouse under individual housing conditions: a potentially useful animal model for evaluating moisturizing effects.

    PubMed

    Kondo, Taizo; Ohno, Hitoshi; Kondo, Toshio; Shiomoto, Yasuhisa; Momii, Akira

    2005-10-01

    In a previous study, we reported the development of grossly observable dry skin in all of the Naruto Research Institute Otsuka Atrichia (NOA) mice that were housed individually. In the present study, dermal physiological function tests were conducted and the usefulness of this dry skin model for evaluating the efficacy of topical moisturizers was assessed. As a result, we have confirmed a marked reduction in the water content of the stratum corneum in these animals. Therefore, the development of dry skin in the NOA mouse strain under individual housing conditions may be expected to serve as a useful animal model for evaluating topical moisturizers. Specifically, the water content of the stratum corneum was restored in proportion to the oil content of the ointment base used to treat the animals, and the moisturizing effects of urea were confirmed in animals treated with urea-containing ointment. In addition, when the animals that had been housed individually were returned to group housing conditions, the water content of the stratum corneum was restored, with a corresponding improvement in dry skin. This finding suggests that socio-psychological factors are involved in the etiology of dry skin in individually housed NOA mice.

  4. Sonic hedgehog increases the skin wound-healing ability of mouse embryonic stem cells through the microRNA 200 family

    PubMed Central

    Suh, Han Na; Han, Ho Jae

    2015-01-01

    Background and Purpose To use stem cell therapy effectively, it is important to enhance the therapeutic potential of stem cells with soluble factors. Although sonic hedgehog (shh) is important in maintaining the stem cell, the recovery effect of mouse embryonic stem cells (mESCs) with shh has not yet been elucidated. The present study investigated the effect of mESCs with shh in skin recovery in vivo as well as the related intracellular signal pathways in vitro. Experimental Approach The healing effect of mESCs with shh on skin wounds was examined in vivo in ICR mice. The involvement of Smads, the microRNA (miR)-200 family, zinc finger E-box-binding homeobox (ZEBs) and E-cadherin on shh-induced mESC migration and self-renewal was determined in vitro. Key Results The mESCs with shh increased re-epithelialization and VEGF expression in skin wounds. Shh-treated mESCs increased both secreted and intracellular levels of VEGF. Shh induced dephosphorylation of glycogen synthase kinase 3β through the Smoothened receptor and increased the phosphorylation of Smad1 and Smad2/3 in mESCs. Shh-induced decrease of the mmu-miR-141, -200c, -200a, -200b and -429 expression levels was significantly reversed by Smad4 siRNA. Shh increased nuclear expression of ZEB1/ZEB2 and decreased E-cadherin expression while increasing cell migration and skin wound healing. Both these effects were reversed by mmu-miR-141 and -200b mimics. Conclusions and Implications Mouse ESCs accelerated skin wound healing by shh through down-regulating E-cadherin, an effect dependent on mmu-miR-141 and -200b. Our data provides evidence for the effectiveness of shh in stem cell-based therapy in vivo. PMID:25257936

  5. Silibinin inhibits ultraviolet B radiation-induced DNA-damage and apoptosis by enhancing interleukin-12 expression in JB6 cells and SKH-1 hairless mouse skin.

    PubMed

    Narayanapillai, Sreekanth; Agarwal, Chapla; Deep, Gagan; Agarwal, Rajesh

    2014-06-01

    Recent studies have demonstrated silibinin efficacy against ultraviolet B (UVB)-induced skin carcinogenesis via different mechanisms in cell lines and animal models; however, its role in regulating interleukin-12 (IL-12), an immunomodulatory cytokine that reduces UVB-induced DNA damage and apoptosis, is not known. Here, we report that UVB irradiation causes caspase 3 and PARP cleavage and apoptosis, and addition of recombinant IL-12 or silibinin immediately after UVB significantly protects UVB-induced apoptosis in JB6 cells. IL-12 antibody-mediated blocking of IL-12 activity compromised the protective effects of both IL-12 and silibinin. Both silibinin and IL-12 also accelerated the repair of UVB-caused cyclobutane-pyrimidine dimers (CPDs) in JB6 cells. Additional studies confirmed that indeed silibinin causes a significant increase in IL-12 levels in UVB-irradiated JB6 cells as well as in mouse skin epidermis, and that similar to cell-culture findings, silibinin topical application immediately after UVB exposure causes a strong protection against UVB-induced TUNEL positive cells in epidermis possibly through a significantly accelerated repair of UVB-caused CPDs. Together, these findings for the first time provide an important insight regarding the pharmacological mechanism wherein silibinin induces endogenous IL-12 in its efficacy against UVB-caused skin damages. In view of the fact that an enhanced endogenous IL-12 level could effectively remove UVB-caused DNA damage and associated skin cancer, our findings suggest that the use of silibinin in UVB-damaged human skin would also be a practical and translational strategy to manage solar radiation-caused skin damages as well as skin cancer.

  6. Overexpression of CRABPI in suprabasal keratinocytes enhances the proliferation of epidermal basal keratinocytes in mouse skin topically treated with all-trans retinoic acid.

    PubMed

    Tang, Xiao-Han; Vivero, Marina; Gudas, Lorraine J

    2008-01-01

    We investigated whether ectopic expression of CRABPI, a cellular retinoic acid binding protein, influenced the actions of all-trans retinoic acid (ATRA) in transgenic (TG) mice. We targeted CRABPI to the basal vs. suprabasal layers of mouse epidermis by using the keratin 14 (K14) and keratin 10 (K10) promoters, respectively. Greater CRABPI protein levels were detected in the epidermis of adult transgenic(+) mice than in transgenic(-) mice for both transgenes. In adult mouse skin CRABPI overexpression in the basal or suprabasal keratinocytes did not cause morphological abnormalities, but did result in decreased CRABPII mRNA levels. Ectopically overexpressed CRABPI in suprabasal keratinocytes, but not in basal keratinocytes, enhanced the thickening of the epidermis induced by topical ATRA treatments (10 microM, 400 microl for 4 days) by 1.59+/-0.2-fold (p<0.05). ATRA treatment (10 microM) resulted in a 59.9+/-9.8% increase (p<0.05) in the BrdU labeling index in K10/FLAG-CRABPI TG(+) mice vs. TG(-) mice. Retinoid topical treatments reduced p27 and CYP26A1 mRNA levels in TG(+) and TG(-) mouse skin in K14 and K10/FLAG-CRABPI transgenic mice. As epidermal basal keratinocyte proliferation is stimulated by paracrine growth factors secreted by ATRA activated suprabasal keratinocytes, our results indicate that CRABPI overexpression in suprabasal keratinocytes enhances the physiological functions of ATRA.

  7. Overexpression of CRABPI in suprabasal keratinocytes enhances the proliferation of epidermal basal keratinocytes in mouse skin topically treated with all-trans retinoic acid

    SciTech Connect

    Tang, X.-H.; Vivero, Marina; Gudas, Lorraine J.

    2008-01-01

    We investigated whether ectopic expression of CRABPI, a cellular retinoic acid binding protein, influenced the actions of all-trans retinoic acid (ATRA) in transgenic (TG) mice. We targeted CRABPI to the basal vs. suprabasal layers of mouse epidermis by using the keratin 14 (K14) and keratin 10 (K10) promoters, respectively. Greater CRABPI protein levels were detected in the epidermis of adult transgenic(+) mice than in transgenic(-) mice for both transgenes. In adult mouse skin CRABPI overexpression in the basal or suprabasal keratinocytes did not cause morphological abnormalities, but did result in decreased CRABPII mRNA levels. Ectopically overexpressed CRABPI in suprabasal keratinocytes, but not in basal keratinocytes, enhanced the thickening of the epidermis induced by topical ATRA treatments (10 {mu}M, 400 {mu}l for 4 days) by 1.59 {+-} 0.2-fold (p < 0.05). ATRA treatment (10 {mu}M) resulted in a 59.9 {+-} 9.8% increase (p < 0.05) in the BrdU labeling index in K10/FLAG-CRABPI TG(+) mice vs. TG(-) mice. Retinoid topical treatments reduced p27 and CYP26A1 mRNA levels in TG(+) and TG(-) mouse skin in K14 and K10/FLAG-CRABPI transgenic mice. As epidermal basal keratinocyte proliferation is stimulated by paracrine growth factors secreted by ATRA activated suprabasal keratinocytes, our results indicate that CRABPI overexpression in suprabasal keratinocytes enhances the physiological functions of ATRA.

  8. Leptin deficiency-induced obesity exacerbates ultraviolet B radiation-induced cyclooxygenase-2 expression and cell survival signals in ultraviolet B-irradiated mouse skin

    SciTech Connect

    Sharma, Som D.; Katiyar, Santosh K.

    2010-05-01

    Obesity has been implicated in several inflammatory diseases and in different types of cancer. Chronic inflammation induced by exposure to ultraviolet (UV) radiation has been implicated in various skin diseases, including melanoma and nonmelanoma skin cancers. As the relationship between obesity and susceptibility to UV radiation-caused inflammation is not clearly understood, we assessed the role of obesity on UVB-induced inflammation, and mediators of this inflammatory response, using the genetically obese (leptin-deficient) mouse model. Leptin-deficient obese (ob/ob) mice and wild-type counterparts (C57/BL6 mice) were exposed to UVB radiation (120 mJ/cm{sup 2}) on alternate days for 1 month. The mice were then euthanized and skin samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. Here, we report that the levels of inflammatory responses were higher in the UVB-exposed skin of the ob/ob obese mice than those in the UVB-exposed skin of the wild-type non-obese mice. The levels of UVB-induced cyclooxygenase-2 expression, prostaglandin-E{sub 2} production, proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser{sup 473}) were higher in the skin of the ob/ob obese mice than the those in skin of their wild-type non-obese counterparts. Compared with the wild-type non-obese mice, the leptin-deficient obese mice also exhibited greater activation of NF-kappaB/p65 and fewer apoptotic cells in the UVB-irradiated skin. Our study suggests for the first time that obesity in mice is associated with greater susceptibility to UVB-induced inflammatory responses and, therefore, obesity may increase susceptibility to UVB-induced inflammation-associated skin diseases, including the risk of skin cancer.

  9. Lgr5+ stem cells and their progeny in mouse epidermis under regimens of exogenous skin carcinogenesis, and their absence in ensuing skin tumors

    PubMed Central

    van de Glind, Gerline C.; Out, Jacoba J.; Rebel, Heggert G.; Tensen, Cornelis P.; de Gruijl, Frank R.

    2016-01-01

    Actively proliferating Lgr5+ skin stem cells are found deep in the hair follicle (HF). These cells renew the HF and drive its expansion in anagen phase. Their long residence and continuous mitotic activity make them prime candidates to transform into skin tumor-initiating cells. This was investigated by subjecting Lgr5-EGFP-Ires-CreERT2/R26R-LacZ mice (haired and hairless) to chemical and UV carcinogenic regimens. In the course of these regimens Lgr5+ cells (EGFP+) remained exclusively located in HFs, and in deep-seated cysts of hairless skin. In haired mice, progeny of Lgr5+ stem cells (LacZ+ after a pulse of tamoxifen) appeared in the interfollicular epidermis upon UV-induced sunburn and in TPA-induced hyperplasia. In hairless mice the progeny remained located in deep-seated cysts and in HF remnants. Progeny in hairless skin was only detected interfollicularly at a late stage, in between outgrowing tumors. Lgr5+ stem cells were absent in the ultimate tumor masses, and no tumor appeared to be a (clonal) expansion of Lgr5+ cells (52 tumors with tamoxifen at the start of carcinogenesis, 42 tumors with tamoxifen late during tumor outgrowth). In contrast to CD34/K15+ quiescent bulge stem cells, actively proliferating Lgr5+ stem cells do therefore not appear to be tumor drivers in experimental skin carcinogenesis. PMID:27409834

  10. The genotoxic air pollutant 3-nitrobenzanthrone and its reactive metabolite N-hydroxy-3-aminobenzanthrone lack initiating and complete carcinogenic activity in NMRI mouse skin.

    PubMed

    Schmeiser, Heinz H; Fürstenberger, Gerhard; Takamura-Enya, Takeji; Phillips, David H; Arlt, Volker M

    2009-10-18

    3-Nitrobenzanthrone (3-NBA), a genotoxic mutagen found in diesel exhaust and ambient air pollution and its active metabolite N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) were tested for initiating and complete carcinogenic activity in the NMRI mouse skin carcinogenesis model. Both compounds were found to be inactive as either tumour initiators or complete carcinogens in mouse skin over a dose range of 25-400nmol. Topical application of 3-NBA and N-OH-3-ABA produced DNA adduct patterns in epidermis, detected by (32)P-postlabelling, similar to those found previously in other organs of rats and mice. 24h after a single treatment of 100nmol DNA adduct levels produced by 3-NBA (18+/-4 adducts/10(8) nucleotides) were 6 times lower than those by 7,12-dimethylbenz[a]anthracene (DMBA; 114+/-37 adducts/10(8) nucleotides). In contrast, identical treatment with N-OH-3-ABA resulted in adduct levels in the same range as with DMBA (136+/-25 adducts/10(8) nucleotides), indicating that initial DNA adduct levels do not parallel tumour initiating activity. When compounds were tested for tumour initiating activity by a single treatment followed by twice-weekly applications of TPA, DNA adducts formed by DMBA, but not by 3-NBA or N-OH-3-ABA, were still detectable 40weeks after treatment. When tested for activity as complete carcinogens by twice-weekly topical application, 3-NBA and N-OH-3-ABA produced identical DNA adduct profiles in mouse skin, with adducts still detectable after 40weeks. Only 3-NBA produced detectable adducts in other organs.

  11. Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

    PubMed Central

    Chakravarti, D; Pelling, J C; Cavalieri, E L; Rogan, E G

    1995-01-01

    Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G-->T and A-->T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo[a,l]pyrene (DB[a,l]P), DB[a,l]P-11,12-dihydrodiol, anti-DB[a,l]P-11,12-diol-13,14-epoxide, DB[a,l]P-8,9-dihydrodiol, 7,12-dimethylbenz[a]anthracene (DMBA), and 1,2,3,4-tetrahydro-DMBA consistently induced a CAA-->CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC-->GTC mutation in codon 13 in 54% of tumors and a CAA-->CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sites generated by loss of hydrocarbon-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin. PMID:7479797

  12. Angiotensin-converting enzyme inhibitor (enalapril maleate) accelerates recovery of mouse skin from UVB-induced wrinkles

    SciTech Connect

    Matsuura-Hachiya, Yuko; Arai, Koji Y.; Ozeki, Rieko; Kikuta, Ayako; Nishiyama, Toshio

    2013-12-06

    Highlights: •Angiotensin converting enzyme (ACE) increases in UVB-irradiated skin. •Administration of an ACE inhibitor improved UVB-induced skin wrinkle. •ACE inhibitor improved UVB-induced epidermal hypertrophy. •ACE inhibitor improved transepidermal water loss in the UVB-irradiated skin. -- Abstract: Angiotensin-converting enzyme (ACE) activity and angiotensin II signaling regulate cell proliferation, differentiation, and tissue remodeling, as well as blood pressure, while in skin, angiotensin II signaling is involved in wound healing, inflammation, and pathological scar formation. Therefore, we hypothesized that angiotensin II is also involved in photoaging of skin. In this study, we examined the effect of enalapril maleate, an ACE inhibitor, on recovery of wrinkled skin of hairless mice exposed to long-term UVB irradiation. Immunohistochemical observation revealed that expression of ACE, angiotensin II, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the skin was increased after UVB irradiation (3 times/week at increasing intensities for 8 weeks). Administration of enalapril maleate (5 times/week for 6 weeks, starting 1 week after 10-week irradiation) accelerated recovery from UVB-induced wrinkles, epidermal hyperplasia and epidermal barrier dysfunction, as compared with the vehicle control. Our results indicate that ACE and angiotensin II activity are involved in skin photoaging, and suggest that ACE inhibitor such as enalapril maleate may have potential for improvement of photoaged skin.

  13. Sterol and triterpene derivatives from plants inhibit the effects of a tumor promoter, and sitosterol and betulinic acid inhibit tumor formation in mouse skin two-stage carcinogenesis.

    PubMed

    Yasukawa, K; Takido, M; Matsumoto, T; Takeuchi, M; Nakagawa, S

    1991-01-01

    A single topical application of 1 microgram of 12-O-tetradecanoylphorbol- 13-acetate (TPA) to the ears of mice was shown to induce edema, and this TPA-induced inflammation was inhibited by 4-methylsterol and triterpene derivatives. The ED50 of these compounds against TPA-induced inflammation was 0.1-3 mumol. Phytosterols had only slight inhibitory effects. Furthermore, application of 5 micrograms TPA to mouse skin rapidly caused accumulation of ornithine decarboxylase (ODC). Similarly, sitosterol and lupane-type triterpene derivatives markedly inhibited this TPA-induced ODC accumulation. In addition, 5 mumol betulinic acid markedly inhibited the promoting effect of 2.5 micrograms TPA applied twice weekly on skin tumor formation in mice initiated with 50 micrograms of 7,12-dimethylbenz[a]anthracene, and 5 mumol of sitosterol caused slight suppression. Thus, the inhibitory effects of sterol and triterpene derivatives on TPA-induced inflammation roughly parallelled their inhibitory activities against tumor promotion.

  14. Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin

    PubMed Central

    Rahman, Shakilur; Ansari, Rizwan Ahmed; Rehman, Hasibur; Parvez, Suhel; Raisuddin, Sheikh

    2011-01-01

    Nordihydroguaiaretic acid (NDGA) is a phenolic antioxidant found in the leaves and twigs of the evergreen desert shrub, Larrea tridentata (Sesse and Moc. ex DC) Coville (creosote bush). It has a long history of traditional medicinal use by the Native Americans and Mexicans. The modulatory effects of topically applied NDGA was studied on acute inflammatory and oxidative stress responses in mouse skin induced by stage I tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). Double TPA treatment adversely altered many of the marker responses of stage I skin tumor promotion cascade. Pretreatment of NDGA in TPA-treated mice mitigated cutaneous lipid peroxidation and inhibited production of hydrogen peroxide. NDGA treatment also restored reduced glutathione level and activities of antioxidant enzymes. Elevated activities of myeloperoxidase, xanthine oxidase and skin edema formation in TPA-treated mice were also lowered by NDGA indicating a restrained inflammatory response. Furthermore, results of histological study demonstrated inhibitory effect of NDGA on cellular inflammatory responses. This study provides a direct evidence of antioxidative and anti-inflammatory properties of NDGA against TPA-induced cutaneous inflammation and oxidative stress corroborating its chemopreventive potential against skin cancer. PMID:19861506

  15. Peroxidized cholesterol-induced matrix metalloproteinase-9 activation and its suppression by dietary beta-carotene in photoaging of hairless mouse skin.

    PubMed

    Minami, Yuko; Kawabata, Kyuichi; Kubo, Yoshiaki; Arase, Seiji; Hirasaka, Katsuya; Nikawa, Takeshi; Bando, Noriko; Kawai, Yoshichika; Terao, Junji

    2009-05-01

    The activation of matrix metalloproteinase (MMP)-9 leading to the formation of wrinkle and sagging of skin is an essential step in the skin photoaging on exposure to ultraviolet A (UVA). This study attempted to elucidate the role of peroxidized cholesterol including cholesterol hydroperoxides (Chol-OOHs), primary products of lipid peroxidation in biomembranes, in MMP-9 activation and the effect of dietary beta-carotene in MMP-9 activation. Hairless mice were subjected to periodic UVA irradiation for 8 weeks. The amount of peroxidized cholesterol detected as total hydroxycholesterol in the skin was increased significantly by the exposure. The activity and protein level of MMP-9 were elevated with wrinkling and sagging formation. MMP-9 activity was also enhanced by the intracutaneous injection of Chol-OOHs into the mouse skin. Adding beta-carotene to the diet of the mice during the period of irradiation suppressed the activity and expression of MMP-9 as well as the wrinkling and sagging formation. The amount of cholesterol 5alpha-hydroperoxide, a singlet molecular oxygen oxygenation-specific peroxidized cholesterol, was significantly lowered by the addition of beta-carotene to the diet. These results strongly suggest that Chol-OOHs formed on exposure to UVA contribute to the expression of MMP-9, resulting in photoaging. Dietary beta-carotene prevents the expression of MMP-9, at least partly, by inhibiting photodynamic action involved in the formation of Chol-OOHs.

  16. The role of placenta-derived mesenchymal stem cells in healing of induced full-thickness skin wound in a mouse model.

    PubMed

    Abd-Allah, Somia H; El-Shal, Amal S; Shalaby, Sally M; Abd-Elbary, Eman; Mazen, Nehad F; Abdel Kader, Rania R

    2015-09-01

    We examined the effect of placenta-derived MSCs (PDMSCs) injection intraregionally and intraperitoneally on healing of induced full thickness mice skin wounds; moreover, the mechanisms by which MSCs exert their effects were also studied. Sixty female mice were divided into three groups after induction of full thickness skin wound; untreated group, wounded mice were injected with MSCs derived from human placenta intraperitoneally or intraregionally. Skin biopsies were obtained 7 and 12 days after wound incision for histological examinations, detection of vascular endothelial growth factor (VEGF) by ELISA, and estimation of expression of mouse ICAM-1, Integrin β1, Integrin β3 genes and human albumin and GAPDH genes by reverse transcription polymerase chain reaction. Human placenta derived-MSCs treated groups showed accelerated wound healing than non-treated group. VEGF, Integrin β1, and Integrin β3 levels were significantly increased in the intraregionally and intraperitoneally treated mice as compared to non-treated group at day 7 after wound induction. ICAM-1 showed significant decrease in its expression in treated groups compared with non-treated group. Interestingly, the intraperitoneal MSCs injections showed better results than intraregional one. PDMSCs accelerate full thickness skin wound healing and the intraperitoneal MSCs injections are more effective than intraregional one. MSCs promote wound healing through release of proangiogenic factors as VEGF, increase healing promoting factors as integrin β1 and β3, and decrease proinflammatory cytokines as ICAM-1.

  17. A multistrain probiotic formulation attenuates skin symptoms of atopic dermatitis in a mouse model through the generation of CD4+Foxp3+ T cells

    PubMed Central

    Shin, Joo-Hyun; Chung, Myung-Jun; Seo, Jae-Gu

    2016-01-01

    Background Atopic dermatitis (AD) is characterized by chronic inflammation of the skin. AD develops mainly in infants and young children. It induces skin disorders and signals the initiation of the allergic march including allergic asthma and rhinitis. Probiotics modify intestinal microbial populations in a beneficial way for human and animal hosts by reducing inflammatory cytokines. Objective As a result of their immunomodulatory properties, probiotics have been considered a promising therapeutic option for the prevention and treatment of AD. Design In this study, we examined the effects of GI7, a potential probiotic mixture consisting of seven strains of bifidobacteria and lactic acid bacteria, on AD in a mouse model. Results Administration of GI7 for 8 weeks reduced AD-like skin lesions and induced changes in the levels of serum markers such as immunoglobulin E and cytokines related to T helper (Th)1 and Th2 cells, and in skin barrier genes. Alleviation of AD seems to be associated with GI7-induced generation of CD4+Foxp3+ regulatory T cells. Conclusions The probiotic mixture may have potential to improve symptoms of AD. PMID:27802847

  18. Pomegranate fruit extract inhibits UVB-induced inflammation and proliferation by modulating NF-κB and MAPK signaling pathways in mouse skin.

    PubMed

    Khan, Naghma; Syed, Deeba N; Pal, Harish Chandra; Mukhtar, Hasan; Afaq, Farrukh

    2012-01-01

    There is considerable interest in the identification of natural agents capable of affording protection to skin from the adverse effects of solar ultraviolet B (UVB) radiation. Pomegranate (Punica granatum L.) fruit possesses as strong antioxidant, anti-inflammatory and antiproliferative properties. Recently, we have shown that oral feeding of pomegranate fruit extract (PFE) to mice afforded substantial protection from the adverse effects of single UVB radiation via modulation in early biomarkers of photocarcinogenesis. This study was designed to investigate the photochemopreventive effects of PFE (0.2%, wt/vol) after multiple UVB irradiations (180 mJ cm(-2), on alternative day, for a total of seven treatments) to the skin of SKH-1 hairless mice. Oral feeding of PFE to SKH-1 mice inhibited UVB-induced epidermal hyperplasia, infiltration of leukocytes, protein oxidation and lipid peroxidation. Immunoblot analysis demonstrated that oral feeding of PFE to mice inhibited UVB-induced (1) nuclear translocation and phosphorylation of nuclear factor kappa B/p65, (2) phosphorylation and degradation of IκBα, (3) activation of IKKα/ΙΚΚβ and (4) phosphorylation of mitogen-activated protein kinase proteins and c-Jun. PFE consumption also inhibited UVB-induced protein expression of (1) COX-2 and iNOS, (2) PCNA and cyclin D1 and (3) matrix metalloproteinases-2,-3 and -9 in mouse skin. Taken together, these data show that PFE consumption afforded protection to mouse skin against the adverse effects of UVB radiation by modulating UVB-induced signaling pathways.

  19. Potent suppressive effect of a Japanese edible seaweed, Enteromorpha prolifera (Sujiao-nori) on initiation and promotion phases of chemically induced mouse skin tumorigenesis.

    PubMed

    Higashi-Okai, K; Otani, S; Okai, Y; Hiqashi-Okaj, K

    1999-06-01

    Potent antigenotoxic and anti-tumor promoting activities of a Japanese edible seaweed, Enteromorpha prolifera (Sujiao-nori in Japanese) were previously identified using an in vitro cell culture experiment (Y. Okai, K. Higashi-Okai, S. Nakamura, Y. Yano, S. Otani, Cancer Lett. 87 (1994) 25-32). However, in vivo anti-carcinogenic activity of this seaweed has not been elucidated until now. In the present study, the anticarcinogenic activity of E. prolifera was analyzed using an initiation and promotion model experiment of mouse skin tumorigenesis caused by 7,12-dimethylbenz[a]anthracene (initiator) and 12-O-tetradecanoylphorbol-13-acetate (promoter). (1) Application of the extract of E. prolifera prior to the treatment with a tumor initiator or promoter caused a significant suppression against skin tumorigenesis, and the combined application of the extract prior to both treatments with initiator and promoter exhibited much stronger suppression against the same skin tumorigenesis. (2) As a possible active principle for the anticarcinogenic activity of the extract, we propose a chlorophyll-related compound, pheophytin-a, which has been recently identified in the extract of this alga as an antigenotoxic substance (Y. Okai, K. Higashi-Okai, J. Sci. Food Agric. 74 (1997) 531-535), and showed significant suppressive effects in the same tumorigenesis experiment. These results suggest that E. prolifera has a potent suppressive activity against chemically induced mouse skin tumorigenesis through the suppression at the initiation and promotion phases, and that pheophytin-a might be partially associated with the in vivo anticarcinogenic activity.

  20. Gene Expression Architecture of Mouse Dorsal and Tail Skin Reveals Functional Differences in Inflammation and Cancer | Office of Cancer Genomics

    Cancer.gov

    Inherited germline polymorphisms can cause gene expression levels in normal tissues to differ substantially between individuals. We present an analysis of the genetic architecture of normal adult skin from 470 genetically unique mice, demonstrating the effect of germline variants, skin tissue location, and perturbation by exogenous inflammation or tumorigenesis on gene signaling pathways.

  1. Daily intake of Jeju groundwater improves the skin condition of the model mouse for human atopic dermatitis.

    PubMed

    Tanaka, Akane; Jung, Kyungsook; Matsuda, Akira; Jang, Hyosun; Kajiwara, Naoki; Amagai, Yosuke; Oida, Kumiko; Ahn, Ginnae; Ohmori, Keitaro; Kang, Kyung-goo; Matsuda, Hiroshi

    2013-03-01

    Drinking water is an important nutrient for human health. The mineral ingredients included in drinking water may affect the physical condition of people. Various kinds of natural water are in circulation as bottled water in developed countries; however, its influence on clinical conditions of patients with certain diseases has not been fully evaluated. In this study, effects of the natural groundwater from Jeju Island on clinical symptoms and skin barrier function in atopic dermatitis (AD) were evaluated. NC/Tnd mice, a model for human AD, with moderate to severe dermatitis were used. Mice were given different natural groundwater or tap water for 8 weeks from 4 weeks of age. Clinical skin severity scores were recorded every week. Scratching analysis and measurement of transepidermal water loss were performed every other week. The pathological condition of the dorsal skin was evaluated histologically. Real-time polymerase chain reaction analysis was performed for cytokine expression in the affected skin. The epidermal hyperplasia and allergic inflammation were reduced in atopic mice supplied with Jeju groundwater when compared to those supplied with tap water or other kinds of natural groundwater. The increase in scratching behavior with the aggravation of clinical severity of dermatitis was favorably controlled. Moreover, transepidermal water loss that reflects skin barrier function was recovered. The early inflammation and hypersensitivity in the atopic skin was alleviated in mice supplied with Jeju groundwater, suggesting its profitable potential on the daily care of patients with skin troubles including AD.

  2. Sarcophine-Diol, a Skin Cancer Chemopreventive Agent, Inhibits Proliferation and Stimulates Apoptosis in Mouse Melanoma B16F10 Cell Line

    PubMed Central

    Szymanski, Pawel T.; Kuppast, Bhimanna; Ahmed, Safwat A.; Khalifa, Sherief; Fahmy, Hesham

    2011-01-01

    Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B16F10 cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B16F10 tumor cells. PMID:22363217

  3. Sarcophine-diol, a skin cancer chemopreventive agent, inhibits proliferation and stimulates apoptosis in mouse melanoma B₁₆F₁₀ cell line.

    PubMed

    Szymanski, Pawel T; Kuppast, Bhimanna; Ahmed, Safwat A; Khalifa, Sherief; Fahmy, Hesham

    2012-01-01

    Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B₁₆F₁₀ cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B₁₆F₁₀ tumor cells.

  4. The risk of hydroquinone and sunscreen over-absorption via photodamaged skin is not greater in senescent skin as compared to young skin: nude mouse as an animal model.

    PubMed

    Hung, Chi-Feng; Chen, Wei-Yu; Aljuffali, Ibrahim A; Shih, Hui-Chi; Fang, Jia-You

    2014-08-25

    Intrinsic aging and photoaging modify skin structure and components, which subsequently change percutaneous absorption of topically applied permeants. The purpose of this study was to systematically evaluate drug/sunscreen permeation via young and senescent skin irradiated by ultraviolet (UV) light. Both young and senescent nude mice were subjected to UVA (10 J/cm(2)) and/or UVB radiation (175 mJ/cm(2)). Physiological parameters, immunohistology, and immunoblotting were employed to examine the aged skin. Hydroquinone and sunscreen permeation was determined by in vitro Franz cell. In vivo skin absorption was documented using a hydrophilic dye, rhodamine 123 (log P=-0.4), as a permeant. UVA exposure induced cyclooxygenase (COX)-2 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) upregulation. Epidermal tight junction (TJ) were degraded by UVA. UVB increased transepidermal water loss (TEWL) from 13 to 24 g/m(2)/h. Hyperplasia and inflammation, but not loss of TJ, were also observed in UVB-treated skin. UVA+UVB- and UVA-irradiated skin demonstrated similar changes in histology and biomarkers. UVA+UVB or UVA exposure increased hydroquinone flux five-fold. A negligible alteration of hydroquinone permeation was shown with UVB exposure. Hydroquinone exhibited a lower penetration through senescent skin than young skin. Both UVA and UVB produced enhancement of oxybenzone flux and skin uptake. However, the amount of increase was less than that of hydroquinone delivery. Photoaging did not augment skin absorption of sunscreens with higher lipophilicity, including avobenzone and ZnO. Exposure to UVA generally increased follicular entrance of these permeants, which showed two- to three-fold greater follicular uptake compared to the untreated group. Photoaging had less impact on drug/sunscreen absorption with more lipophilic permeants. Percutaneous absorption did not increase in skin subjected to both intrinsic and extrinsic aging.

  5. Induction of granulocyte-macrophage colony-stimulating activity in mouse skin by inflammatory agents and tumor promoters.

    PubMed Central

    Koury, M J; Balmain, A; Pragnell, I B

    1983-01-01

    The granulocyte-macrophage colony stimulating activity (GM-CSA) was assayed in acetic acid extracts of skin from mice which were topically treated with inflammatory and tumor-promoting diterpene esters. Extremely large increases in GM-CSA were found in skin treated with the strongly tumor-promoting 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the weakly promoting mezerein, while only a very slight increase was found with the non-promoting 4-O-methyl-TPA (4-OMe-TPA). Untreated areas of skin had very little GM-CSA. In the treated skins, the elevated GM-CSA was noted within a few hours and lasted for greater than 24 h after treatment. Although the levels of GM-CSA induced in the skin correspond to the degree of inflammation elicited by the respective treatments, the leukocytes in the acute inflammatory infiltrate did not appear to be responsible for the increased GM-CSA. Both epidermis and dermis had increased GM-CSA following TPA treatment of skin. Treatment of fibroblast and epithelial continuous cell lines with diterpene esters resulted in a similar pattern of GM-CSA induction in their supernatant media as that noted in the skin extracts. A large majority of the colonies stimulated by the diterpene-ester induced GM-CSA were composed of only macrophages. The results demonstrate that the topical administration of an inflammatory diterpene ester results in a rapid, marked yet local GM-CSA induction in the skin of treated mice. This indirect action in which diterpene esters induce in certain cells a growth regulatory factor for other types of cells may be an important element in carcinogenesis. Images Fig. 2. PMID:6605850

  6. Populations of p53 codon 270 CGT to TGT mutant cells in SKH-1 mouse skin tumors induced by simulated solar light.

    PubMed

    Verkler, Tracie L; Delongchamp, Robert R; Couch, Letha H; Miller, Barbara J; Warbritton, Alan; Mellick, Paul W; Howard, Paul C; Parsons, Barbara L

    2008-11-01

    The p53 codon 270 CGT to TGT mutation was investigated as a biomarker of sunlight-induced mutagenesis and carcinogenesis. The relationship between tumor development and abundance of this hotspot mutation was analyzed in mouse skin tumors induced by chronic exposure to simulated solar light (SSL). The 24 tumors analyzed had similar growth kinetics, with an average doubling time of approximately 16.4 d. Levels of the p53 codon 270 mutation were quantified in the 24 mouse skin tumors using allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). All tumors contained measurable amounts of the mutation. The p53 codon 270 CGT to TGT mutant fraction (MF) ranged from 2.29 x 10(-3) to 9.42 x 10(-2), with 3.26 x 10(-2) as the median. These p53 MF measurements are lower than expected for an initiating mutation involved in the development of tumors of monoclonal origin. There was no evidence of a correlation between p53 codon 270 MF and either tumor area or an estimate of tumor cell number. Thus, the data do not support the idea that p53 mutation accumulates linearly during tumor development. To investigate how p53 mutation was distributed within tumors, 19 needle biopsies from seven different tumors were analyzed by ACB-PCR. This analysis demonstrated that p53 codon 270 mutation is heterogeneously distributed within tumors. The long-term goal of this research is to combine morphological and p53 MF measurements from tissues corresponding to the various stages of tumor development, in order to derive mathematical models relating the p53 codon 270 mutation to the development of SSL-induced skin tumors.

  7. Hesperidin methyl chalcone inhibits oxidative stress and inflammation in a mouse model of ultraviolet B irradiation-induced skin damage.

    PubMed

    Martinez, Renata M; Pinho-Ribeiro, Felipe A; Steffen, Vinicius S; Caviglione, Carla V; Vignoli, Josiane A; Baracat, Marcela M; Georgetti, Sandra R; Verri, Waldiceu A; Casagrande, Rubia

    2015-07-01

    Hesperidin methyl chalcone (HMC) is a safe flavonoid used to treat chronic venous diseases, but its effects and mechanisms on UVB irradiation-induced inflammation and oxidative stress have never been described in vivo. Thus, the purpose of this study was to evaluate the effects of systemic administration of HMC in skin oxidative stress and inflammation induced by UVB irradiation. To induce skin damage, hairless mice were exposed to an acute UVB irradiation dose of 4.14 J/cm(2), and the dorsal skin samples were collected to evaluate oxidative stress and inflammatory response. The intraperitoneal treatment with HMC at the dose of 300 mg/kg inhibited UVB irradiation-induced skin edema, neutrophil recruitment, and matrix metalloproteinase-9 activity. HMC also protected the skin from UVB irradiation-induced oxidative stress by maintaining ferric reducing antioxidant power (FRAP), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS) scavenging ability and antioxidant levels (reduced glutathione and catalase). Corroborating, HMC inhibited UVB irradiation-induced superoxide anion generation and gp91phox (NADPH oxidase subunit) mRNA expression. Furthermore, the antioxidant effect of HMC resulted in lower production of inflammatory mediators, including lipid hydroperoxides and a wide range of cytokines. Taken together, these results unveil a novel applicability of HMC in the treatment of UVB irradiation-induced skin inflammation and oxidative stress.

  8. Antibacterial activity and therapeutic efficacy of Fl-P(R)P(R)P(L)-5, a cationic amphiphilic polyproline helix, in a mouse model of staphylococcal skin infection.

    PubMed

    Thangamani, Shankar; Nepal, Manish; Chmielewski, Jean; Seleem, Mohamed N

    2015-01-01

    The antibacterial activities and therapeutic efficacy of the cationic, unnatural proline-rich peptide Fl-P(R)P(R)P(L)-5 were evaluated against multidrug-resistant Staphylococcus aureus in a mouse model of skin infection. Fl-P(R)P(R)P(L)-5 showed potent activity against all clinical isolates of S. aureus tested, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA, respectively). Fl-P(R)P(R)P(L)-5 was also superior in clearing established in vitro biofilms of S. aureus and Staphylococcus epidermidis, compared with the established antimicrobials mupirocin and vancomycin. Additionally, topical treatment of an MRSA-infected wound with Fl-P(R)P(R)P(L)-5 enhanced wound closure and significantly reduced bacterial load. Finally, 0.5% Fl-P(R)P(R)P(L)-5 significantly reduced the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in wounds induced by MRSA skin infection. In conclusion, the results of this study suggest the potential application of Fl-P(R)P(R)P(L)-5 in the treatment of staphylococcal skin infections.

  9. Photoactivation of ROS production in situ transiently activates cell proliferation in mouse skin and in the hair follicle stem cell niche promoting hair growth and wound healing

    PubMed Central

    Carrasco, Elisa; Calvo, María I.; Blázquez-Castro, Alfonso; Vecchio, Daniela; Zamarrón, Alicia; de Almeida, Irma Joyce Dias; Stockert, Juan C.; Hamblin, Michael R.; Juarranz, Ángeles; Espada, Jesús

    2015-01-01

    The role of reactive oxygen species (ROS) in the regulation of hair follicle cycle and skin homeostasis is poorly characterized. ROS have been traditionally linked to human disease and ageing, but recent findings suggest that can also have beneficial physiological functions in vivo in mammals. To test this hypothesis, we transiently switched on in situ ROS production in mouse skin. This process activated cell proliferation in the tissue and, interestingly, in the bulge region of the hair follicle, a major reservoir of epidermal stem cells, promoting hair growth as well as stimulating tissue repair after severe burn injury. We further show that these effects were associated with a transient Src kinase phosphorylation at Tyr416 and with a strong transcriptional activation of the prolactin family 2 subfamily c of growth factors. Our results point to potentially relevant modes of skin homeostasis regulation and demonstrate that a local and transient ROS production can regulate stem cell and tissue function in the whole organism. PMID:26134949

  10. The FYVE domain of Smad Anchor for Receptor Activation (SARA) is required to prevent skin carcinogenesis, but not in mouse development.

    PubMed

    Chang, Huang-Ming; Lin, Yu-Ying; Tsai, Pei-Chun; Liang, Chung-Tiang; Yan, Yu-Ting

    2014-01-01

    Smad Anchor for Receptor Activation (SARA) has been reported as a critical role in TGF-β signal transduction by recruiting non-activated Smad2/3 to the TGF-β receptor and ensuring appropriate subcellular localization of the activated receptor-bound complex. However, controversies still exist in previous reports. In this study, we describe the expression of two SARA isoforms, SARA1 and SARA2, in mice and report the generation and characterization of SARA mutant mice with FYVE domain deletion. SARA mutant mice developed normally and showed no gross abnormalities. Further examination showed that the TGF-β signaling pathway was indeed altered in SARA mutant mice, with the downregulation of Smad2 protein expression. The decreasing expression of Smad2 was caused by enhancing Smurf2-mediated proteasome degradation pathway. However, the internalization of TGF-β receptors into the early endosome was not affected in SARA mutant mouse embryonic fibroblasts (MEFs). Moreover, the downregulation of Smad2 in SARA mutant MEFs was not sufficient to disrupt the diverse cellular biological functions of TGF-β signaling, including growth inhibition, apoptosis, senescence, and the epithelial-to-mesenchymal transition. Our results indicate that SARA is not involved in the activation process of TGF-β signal transduction. Using a two-stage skin chemical carcinogenesis assay, we found that the loss of SARA promoted skin tumor formation and malignant progression. Our data suggest a protective role of SARA in skin carcinogenesis.

  11. Chemical Characterization and Toxicologic Evaluation of Airborne Mixtures. Tumorigenicity Studies of Diesel Fuel-2, Red Smoke Dye and Violet Smoke Dyes in the SENCAR Mouse Skin Tumorigenesis Bioassay System

    DTIC Science & Technology

    1985-09-01

    nitrosamides, sulfonates, sultones, and ureas. The 32 chemicals listed in Table 1 include such well known chemical carcino- gens as aflatoxin BI, bis...direct or indirect carcinogen at a subthreshold dose and is essentially irreversible. The promotion phase requires repetitive treatments after...34by initiators of mouse skin tumorigenesis. Cancer Res. 29: 510-514. Hennings, H., B. Michael, and E. Patterson. 1978. Croton oil enhancement of skin

  12. Transplanted bone marrow-derived circulating PDGFRα+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa mouse skin graft.

    PubMed

    Iinuma, Shin; Aikawa, Eriko; Tamai, Katsuto; Fujita, Ryo; Kikuchi, Yasushi; Chino, Takenao; Kikuta, Junichi; McGrath, John A; Uitto, Jouni; Ishii, Masaru; Iizuka, Hajime; Kaneda, Yasufumi

    2015-02-15

    Recessive dystrophic epidermolysis bullosa (RDEB) is an intractable genetic blistering skin disease in which the epithelial structure easily separates from the underlying dermis because of genetic loss of functional type VII collagen (Col7) in the cutaneous basement membrane zone. Recent studies have demonstrated that allogeneic bone marrow transplantation (BMT) ameliorates the skin blistering phenotype of RDEB patients by restoring Col7. However, the exact therapeutic mechanism of BMT in RDEB remains unclear. In this study, we investigated the roles of transplanted bone marrow-derived circulating mesenchymal cells in RDEB (Col7-null) mice. In wild-type mice with prior GFP-BMT after lethal irradiation, lineage-negative/GFP-positive (Lin(-)/GFP(+)) cells, including platelet-derived growth factor receptor α-positive (PDGFRα(+)) mesenchymal cells, specifically migrated to skin grafts from RDEB mice and expressed Col7. Vascular endothelial cells and follicular keratinocytes in the deep dermis of the skin grafts expressed SDF-1α, and the bone marrow-derived PDGFRα(+) cells expressed CXCR4 on their surface. Systemic administration of the CXCR4 antagonist AMD3100 markedly decreased the migration of bone marrow-derived PDGFRα(+) cells into the skin graft, resulting in persistent epidermal detachment with massive necrosis and inflammation in the skin graft of RDEB mice; without AMD3100 administration, Col7 was significantly supplemented to ameliorate the pathogenic blistering phenotype. Collectively, these data suggest that the SDF1α/CXCR4 signaling axis induces transplanted bone marrow-derived circulating PDGFRα(+) mesenchymal cells to migrate and supply functional Col7 to regenerate RDEB skin.

  13. Systemic component of protoporphyrin IX production in nude mouse skin upon topical application of aminolevulinic acid depends on the application conditions.

    PubMed

    van den Akker, Johanna T H M; Iani, Vladimir; Star, Willem M; Sterenborg, Henricus J C M; Moan, Johan

    2002-02-01

    Topical application of 5-aminolevulinic acid (ALA) for protoporphyrin IX (PpIX)-based photodynamic therapy of skin cancer is generally considered not to induce systemic side effects because PpIX is supposed to be formed locally. However, earlier studies with topically applied ALA have revealed that in mice PpIX is not only produced in the application area but also in other organs including skin outside the application area, whereas esterified ALA does not. From these results, it was concluded that it is not redistribution of circulating PpIX that causes the fluorescence distant from the ALA application site, but rather, local PpIX production induced by circulating ALA. In the present study we investigate the effects of the ALA concentration in the cream, the application time, the presence of a penetration enhancer, the presence of the stratum corneum and esterification of ALA on the PpIX production in nude mouse skin outside the area where ALA is applied. For this purpose, ALA and ALA hexyl ester (ALAHE) were applied to one flank, and the PpIX fluorescence was measured in the contralateral flank. During a 24 h application of ALA, PpIX was produced in the contralateral flank. No PpIX could be detected in the contralateral flank after ALA application times ranging from 1 to 60 min. Tape-stripping the skin prior to short-term ALA application, but not the addition of a penetration enhancer, resulted in PpIX production in the contralateral flank. When ALAHE was applied, no PpIX fluorescence was measured in the contralateral flank under any application condition. The results suggest that the systemic component of PpIX production outside the ALA application area plays a minor or no role in relevant clinical situations, when the duration of ALA (ester) application is relatively short and a penetration enhancer is possibly added.

  14. The effects of Origanum hypericifolium essential oil application and ultraviolet B irradiation on mouse skin: An ultrastructural study.

    PubMed

    Ili, Pinar

    2016-07-01

    Exposure to UV radiation can cause histopathological and ultrastructural changes in the skin. Origanum hypericifolium, an endemic Turkish plant,essential oil is mainly composed of monoterpenes. The effects of undiluted O. hypericifolium oil on the ultrastructural characteristics of the UVB-irradiated dorsal skin of mice were investigated using transmission electron microscopy. The BALB/c mice were shaved of dorsal hair and randomly housed into 4 groups: 1: control; 2: UVB-irradiated; 3: oil applied; and 4: oil applied and UVB-irradiated. The oil was applied topically to the dorsal skins of the mice on alternate days for 1week prior to UVB exposure. The skins were irradiated for a total dose of 3.5J/cm(2). The sections were stained with hematoxylin and eosin, semithin sections were stained with toluidine blue and ultrathin sections were contrasted with uranyl acetate/lead citrate. There were histopathological changes such as parakeratosis and squamous hyperplasia in the epidermal cell layers (Groups 3 and 4). There were also ultrastructural changes including lacunae formations throughout the stratum corneum layer (Groups 2, 3, and 4), enlargement of intercellular spaces (Groups 2 and 3), reduced desmosomes, narrow and elongated interdigitations, shortened, relatively indistinct and electron dense intermediate keratin filament bundles (Group 3). There were various sizes of cytoplasmic and perinucleolar vacuoles (Groups 3 and 4) and apoptotic bodies phagocytized by keratinocytes (Group 4). I conclude that undiluted oil has side-effects and the potential to inflict injury to the skin. The oil does not ameliorate the negative effects of UVB on epidermal skin cells.

  15. Effects of C-Phycocyanin on the representative genes of tumor development in mouse skin exposed to 12-O-tetradecanoyl-phorbol-13-acetate.

    PubMed

    Gupta, Naresh Kumar; Gupta, Krishna P

    2012-11-01

    C-Phycocyanin (C-PC), a biliprotein from the sea weed, has been shown to have the beneficial effects like antioxidant, anti-inflammatory, neuroprotective, and hepatoprotective properties and is used as food supplement. We are showing the effect of C-Phycocyanin on the early events altered by tumor promoter. TPA induced the expression of critical events of tumorigenesis like ornithine decarboxylase, cyclooxygenase-2, interleukin-6 and pSTAT3 in mouse skin after 5h of application, whereas expression of transglutaminase2 was decreased at this time point. This TPA-caused altered expression of genes was prevented in presence of C-Phycocyanin. This prevention by C-Phycocyanin appeared to be dependent on the dose of C-Phycocyanin used. The results are useful for the detailed study on the preventive effect of C-Phycocyanin on TPA induced tumor promotion.

  16. Roughness threshold for cell attachment and proliferation on plasma micro-nanotextured polymeric surfaces: the case of primary human skin fibroblasts and mouse immortalized 3T3 fibroblasts

    NASA Astrophysics Data System (ADS)

    Bourkoula, A.; Constantoudis, V.; Kontziampasis, D.; Petrou, P. S.; Kakabakos, S. E.; Tserepi, A.; Gogolides, E.

    2016-08-01

    Poly(methyl methacrylate) surfaces have been micro-nanotextured in oxygen plasmas with increasing ion energy, leading to micro-nanotopography characterized by increased root mean square roughness, correlation length and fractal dimension. Primary human skin fibroblasts and mouse immortalized 3T3 fibroblasts were cultured on these surfaces and the number of adhering cells, their proliferation rate and morphology (cytoplasm and nucleus area) were evaluated as a function of roughness height, correlation length, and fractal dimension. A roughness threshold behavior was observed for both types of cells leading to dramatic cell number decrease above this threshold, which is almost similar for the two types of cells, despite their differences in size and stiffness. The results are discussed based on two theoretical models, which are reconciled and unified when the elastic moduli and the size of the cells are taken into account.

  17. Inhibition of the binding of 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene to DNA in mouse skin epidermis by 1-ethynylpyrene.

    PubMed

    Viaje, A; Lu, J Y; Hopkins, N E; Nettikumara, A N; DiGiovanni, J; Alworth, W L; Slaga, T J

    1990-07-01

    The effects of 1-ethynylpyrene (EP), 1-vinylpyrene (VP) and 2-ethynlnaphthalene (EN) on the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) and of benzo[a]-pyrene (B[a]P) to the epidermal DNA in mouse skin were investigated. When applied topically, 5 min before an initiating dose of 10 nmol DMBA or of 200 nmol B[a]P, EP was an effective inhibitor of the formation of the covalent complexes of these procarcinogenic polycyclic aromatic hydrocarbons (PAHs) with the epidermal DNA. VP, applied under the same conditions, was a significantly less effective inhibitor of the binding of DMBA to DNA and showed even weaker inhibition of the binding of B[a]P. EN was ineffective as an inhibitor of the binding of either DMBA or B[a]P. These results establish that both the pyrene nucleus and the ethynyl substituent of EP contribute to the effective inhibition of the binding of DMBA and B[a]P to the epidermal DNA of mouse skin. No significant changes in the ratios of the anti- to the syndiol epoxide-DNA adducts of DMBA or of B[a]P were produced by doses of EP that produced inhibitions of the binding to DNA. At doses of VP that inhibited covalent binding of both DMBA and B[a]P, no changes in DMBA-DNA adduct distributions were observed but changes in the relative proportions of several B[a]P-DNA adducts were noted. These data are discussed in terms of the potential of aryl acetylenes to act as suicide inhibitors (mechanism-based inactivators) of cytochrome P450-dependent monooxygenase isozymes.

  18. Retinoic acid promotes the proliferation of primordial germ cell-like cells differentiated from mouse skin-derived stem cells in vitro.

    PubMed

    Tan, Hui; Wang, Jun-Jie; Cheng, Shun-Feng; Ge, Wei; Sun, Yuan-Chao; Sun, Xiao-Feng; Sun, Rui; Li, Lan; Li, Bo; Shen, Wei

    2016-02-01

    Skin-derived stem cells (SDSCs) have the potential to differentiate into gametes and are a potential resource for research and clinical applications. Sufficient amount of primordial germ cells (PGCs) is an important requirement for successful differentiation of SDSCs into gametes in vitro. Retinoic acid (RA), a vitamin A-derived small lipophilic molecule, promotes the growth of PGCs in vivo; however, the role of RA on the proliferation of PGC-like cells (PGCLCs) derived from SDSCs remains unknown. In this study, SDSCs were induced to differentiate into the embryoid body and cocultured with mouse fibroblasts to form PGCLCs. The proliferation of PGCLCs with the presence of various concentrations of RA was investigated in vitro. Immunofluorescence labeling showed that the 5-Bromo-2-deoxyUridine-positive ratio of PGCLCs was increased after the cells were treated with 5-μM RA, and flow cytometry results showed that the number of cells in the S phase was increased significantly. The messenger RNA expression levels of cell cycle-related genes, CCND1 and CDK2, were also increased. Furthermore, RA effectively promoted the external proliferation of endogenous PGCs when 11.5-days postcoitum fetal mouse genital ridges were cultured in vitro. In conclusion, 5-μM RA promoted the proliferation of SDSCs-derived PGCLCs and endogenous PGCs. Our study will provide a valuable model system for studying the differentiation of stem cells into gametes in vitro.

  19. MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes.

    PubMed

    Wang, Pengchao; Zhao, Yuanyuan; Fan, Ruiwen; Chen, Tianzhi; Dong, Changsheng

    2016-06-24

    MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3' untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3' UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF) and Tyrosinase (TYR) were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5.

  20. In-vivo and label-free imaging of cellular and tissue structures in mouse ear skin by using second- and third-harmonic generation microscopy

    NASA Astrophysics Data System (ADS)

    Lee, Eung Jang; Kim, Boram; Ahn, Hong-Gyu; Park, Seung-Han; Cheong, Eunji; Lee, Sangyoup

    2015-02-01

    A video-rate multimodal microscope, which can obtain second- and third- harmonic generation (SHG and THG) images simultaneously, is developed for investigating cellular and tissue structures in mouse ear skin. By utilizing in-vivo video-rate epi-detected SHG and THG microscopy, we successfully demonstrate that combined images of subcutaneous cellular components and peripheral nerve fibers, together with the collagen fiber, in the mouse ear pinna can be obtained without employing fluorescent probes. We also show that the flow of red blood cells and the diameter change of arteriole-like blood vessels can be visualized with femtosecond laser pulses with a wavelength of 1036 nm. In particular, the epi-THG contrast images of the blood-vessel walls display clearly the difference between the arteriole-like and the venule capillary-like blood-vessel types. We should emphasize that our newly-developed microscope system has a unique feature in that it can produce simultaneous in-vivo label-free SHG and THG images in contrast to the conventional confocal and two-photon microscopes.

  1. MicroRNA-21a-5p Functions on the Regulation of Melanogenesis by Targeting Sox5 in Mouse Skin Melanocytes

    PubMed Central

    Wang, Pengchao; Zhao, Yuanyuan; Fan, Ruiwen; Chen, Tianzhi; Dong, Changsheng

    2016-01-01

    MicroRNAs (miRNAs) play an important role in regulating almost all biological processes. miRNAs bind to the 3′ untranslated region (UTR) of mRNAs by sequence matching. In a previous study, we demonstrated that miR-21 was differently expressed in alpaca skin with different hair color. However, the molecular and cellular mechanisms for miR-21 to regulate the coat color are not yet completely understood. In this study, we transfected miR-21a-5p into mouse melanocytes and demonstrated its function on melanogenesis of miR-21a-5p by targeting Sox5, which inhibits melanogenesis in mouse melanocytes. The results suggested that miR-21a-5p targeted Sox5 gene based on the binding site in 3′ UTR of Sox5 and overexpression of miR-21a-5p significantly down-regulated Sox5 mRNA and protein expression. Meanwhile, mRNA and protein expression of microphthalmia transcription factor (MITF) and Tyrosinase (TYR) were up-regulated, which subsequently make the melanin production in melanocytes increased. The results suggest that miR-21a-5p regulates melanogenesis via MITF by targeting Sox5. PMID:27347933

  2. Inhibition of DNA and protein synthesis in UV-irradiated mouse skin by 2-difluoromethylornithine, methylglyoxal bis(guanylhydrazone), and their combination

    SciTech Connect

    Kaepyaho, K.; Lauharanta, J.; Jaenne, J.

    1983-08-01

    Exposure of mouse skin to UVB irradiation greatly enhanced the biosynthesis and accumulation of putrescine and spermidine before or concomitantly with stimulation of epidermal macromolecular (DNA and protein) synthesis. Topical treatment of UV-exposed skin with 2 inhibitors of polyamine biosynthesis, 2-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) (MGBG) prevented the enhanced epidermal accumulation of polyamines, especially spermidine, and also inhibited the incorporation of radioactive precursors into DNA and protein. When applied in combination, these 2 antimetabolites of polyamines produced an inhibition of macromolecular synthesis that was at least additive: (/sup 3/H)thymidine incorporation decreased by 80% and (/sup 14/C)leucine incorporation by 44% as compared with the UVB-irradiated control mice. A slight decrease in the ratio of (/sup 3/H)histidine/(/sup 14/C)leucine incorporation indicated that protein synthesis of the differentiating cell layers was also affected by the inhibitors. The effects of the combined DFMO and MGBG treatment were partially reversed by concomitant topical application of spermidine.

  3. Dual Effects of Bisphosphonates on Ectopic Skin and Vascular Soft Tissue Mineralization versus Bone Microarchitecture in a Mouse Model of Generalized Arterial Calcification of Infancy.

    PubMed

    Li, Qiaoli; Kingman, Joshua; Sundberg, John P; Levine, Michael A; Uitto, Jouni

    2016-01-01

    Generalized arterial calcification of infancy is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate (PPi) levels. We previously characterized the Enpp1(asj) mutant mouse as a model of generalized arterial calcification of infancy, and we have now explored the potential efficacy of bisphosphonates, nonhydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. The mice were maintained on either basic diet (control) or diets containing etidronate or alendronate in three different concentrations (experimental). Considering low bioavailability of bisphosphonates when administered orally, subsequent studies tested the mice with subcutaneous injections of etidronate. The treatments were initiated at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks of age by quantitation of calcium deposits in the muzzle skin containing dermal sheath of vibrissae and in aorta. We found that bisphosphonate treatments significantly reduced mineralization in skin and aorta. These changes in treated mice were accompanied with restoration of their bone microarchitecture, determined by microcomputed tomography. The inhibitory capacity of bisphosphonates, with mechanistic implications, was confirmed in a cell-based mineralization assay in vitro. Collectively, these results suggest that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in generalized arterial calcification of infancy caused by ENPP1 mutations.

  4. Autofluorescence imaging device for real-time detection and tracking of pathogenic bacteria in a mouse skin wound model: preclinical feasibility studies

    NASA Astrophysics Data System (ADS)

    Wu, Yichao Charlie; Kulbatski, Iris; Medeiros, Philip J.; Maeda, Azusa; Bu, Jiachuan; Xu, Lizhen; Chen, Yonghong; DaCosta, Ralph S.

    2014-08-01

    Bacterial infection significantly impedes wound healing. Clinical diagnosis of wound infections is subjective and suboptimal, in part because bacteria are invisible to the naked eye during clinical examination. Moreover, bacterial infection can be present in asymptomatic patients, leading to missed opportunities for diagnosis and treatment. We developed a prototype handheld autofluorescence (AF) imaging device (Portable Real-time Optical Detection, Identification and Guidance for Intervention-PRODIGI) to noninvasively visualize and measure bacterial load in wounds in real time. We conducted preclinical pilot studies in an established nude mouse skin wound model inoculated with bioluminescent Staphylococcus aureus bacteria. We tested the feasibility of longitudinal AF imaging for in vivo visualization of bacterial load in skin wounds, validated by bioluminescence imaging. We showed that bacteria (S. aureus), occult to standard examination, can be visualized in wounds using PRODIGI. We also detected quantitative changes in wound bacterial load over time based on the antibiotic treatment and the correlation of bacterial AF intensity with bacterial load. AF imaging of wounds offers a safe, noninvasive method for visualizing the presence, location, and extent of bacteria as well as measuring relative changes in bacterial load in wounds in real time.

  5. The Immune Response to Skin Trauma Is Dependent on the Etiology of Injury in a Mouse Model of Burn and Excision.

    PubMed

    Valvis, Samantha M; Waithman, Jason; Wood, Fiona M; Fear, Mark W; Fear, Vanessa S

    2015-08-01

    Skin trauma has many different causes including incision, blunt force, and burn. All of these traumas trigger an immune response. However, it is currently unclear whether the immune response is specific to the etiology of the injury. This study was established to determine whether the immune response to excision and burn injury of equivalent extent was the same. Using a mouse model of a full-thickness 19 mm diameter excision or 19 mm diameter full-thickness burn injury, we examined the innate immune response at the level of serum cytokine induction, whole-blood lymphocyte populations, dendritic cell function/phenotype, and the ensuing adaptive immune responses of CD4 and CD8 T-cell populations. Strikingly, both the innate and adaptive immune system responses differed between the burn and excision injuries. Acute cytokine induction was faster and different in profile to that of excision injury, leading to changes in systemic monocyte and neutrophil levels. Differences in the immune profile between burn and excision were also noted up to day 84 post injury, suggesting that the etiology of injury leads to sustained changes in the response. This may in part underlie clinical observations of differences in patient morbidity and mortality in response to different skin injury types.

  6. Protective effects of hemin and tetrakis(4-benzoic acid)porphyrin on bacterial mutagenesis and mouse skin carcinogenesis induced by 7, 12-dimethylbenz[a]anthracene.

    PubMed

    Chung, W Y; Lee, J M; Lee, W Y; Surh, Y J; Park, K K

    2000-12-20

    Porphyrins which are widespread in nature can interfere with the actions of certain carcinogens and mutagens, and have also been used clinically in photodynamic therapy (PDT) of tumors. Porphyrins such as chlorophyll, chlorophyllin (CHL) and hemin are known to inactivate various mutagens by forming complexes with them. Tetrakis(4-benzoic acid)porphyrin (TBAP) has been developed as a photosensitizer for PDT and its metal complex, MnTBAP has been shown to be efficacious in a variety of in vitro and in vivo oxidative stress models of human diseases. In the present study, we have found that TBAP and hemin exert concentration-related inhibition of his(+) reversion in Salmonella typhimurium TA100 induced by 7, 12-dimethylbenz[a]anthracene (DMBA), and significantly reduced both incidence and multiplicity of skin tumors when topically applied prior to treatment of 12-O-tetradecanoylphorbol-13-acetate in female ICR mice. Covalent DNA binding of DMBA in mouse skin was also significantly inhibited by topical application of TBAP or hemin as well as CHL. These results suggest the chemopreventive potential of compounds containing a porphyrin nucleus.

  7. Gene targeting at the mouse cytokeratin 10 locus: severe skin fragility and changes of cytokeratin expression in the epidermis

    PubMed Central

    1996-01-01

    Bullous congenital ichthyosiform erythroderma (BCIE) is a dominantly inherited blistering skin disorder caused by point mutations in the suprabasal cytokeratins 1 or 10. Targeting the murine cytokeratin 10 gene in ES cells resulted in mice with different phenotypes in the homozygotes and heterozygotes; both of which exhibit similarities to specific clinical characteristics of BCIE. Homozygotes suffered from severe skin fragility and died shortly after birth. Heterozygotes were apparently unaffected at birth, but developed hyperkeratosis with age. In both genotypes, aggregation of cytokeratin intermediate filaments, changes in cytokeratin expression, and alterations in the program of epidermal differentiation were observed. In addition we demonstrate, for the first time, the existence of the murine equivalent of human cytokeratin 16. PMID:8603923

  8. An EPR method for estimating activity of antioxidants in mouse skin using an anthralin-derived radical model.

    PubMed

    Kawai, Sayo; Matsumoto, Ken-Ichiro; Utsumi, Hideo

    2010-03-01

    Inhibitory effects of intravenously or orally administered antioxidants on the anthralin-derived radical generated in skin (mainly in the epidermis) of living mice by ultraviolet-A (UVA) irradiation were estimated. Anthralin was applied to the dorsal skin of living mice and the mice were then exposed to UVA. The EPR signal intensity in skin tissue strips obtained from mice after anthralin-UVA treatment was measured by an X-band EPR spectrometer. Several common antioxidants such as ascorbate, glutathione and Trolox (a vitamin E analogue) intravenously administered to mice reduced anthralin-derived radical generation. Trolox showed the most prolonged and powerful effect. Intravenous injection of a clinically used cerebral neuroprotective drug, Edarabone (Radicut), also showed depletion for the anthralin-derived radical. Oral administration of a commercialized nutritional supplement (a cocktail of 17 herbals and vitamins) also attenuated the anthralin-derived radical. The anthralin-UVA treatment model for antioxidant activity in the epidermis is a potentially feasible method to estimate activity of antioxidants in the body.

  9. Fluorescent peptide biosensor for monitoring CDK4/cyclin D kinase activity in melanoma cell extracts, mouse xenografts and skin biopsies.

    PubMed

    Prével, Camille; Pellerano, Morgan; González-Vera, Juan A; Henri, Pauline; Meunier, Laurent; Vollaire, Julien; Josserand, Véronique; Morris, May C

    2016-11-15

    Melanoma constitutes the most aggressive form of skin cancer, which further metastasizes into a deadly form of cancer. The p16(INK4a)-Cyclin D-CDK4/6-pRb pathway is dysregulated in 90% of melanomas. CDK4/Cyclin D kinase hyperactivation, associated with mutation of CDK4, amplification of Cyclin D or loss of p16(INK4a) leads to increased risk of developing melanoma. This kinase therefore constitutes a key biomarker in melanoma and an emerging pharmacological target, however there are no tools enabling direct detection or quantification of its activity. Here we report on the design and application of a fluorescent peptide biosensor to quantify CDK4 activity in melanoma cell extracts, skin biopsies and melanoma xenografts. This biosensor provides sensitive means of comparing CDK4 activity between different melanoma cell lines and further responds to CDK4 downregulation by siRNA or small-molecule inhibitors. By affording means of monitoring CDK4 hyperactivity consequent to cancer-associated molecular alterations in upstream signaling pathways that converge upon this kinase, this biosensor offers an alternative to immunological identification of melanoma-specific biomarkers, thereby constituting an attractive tool for diagnostic purposes, providing complementary functional information to histological analysis, of particular utility for detection of melanoma onset in precancerous lesions. This is indeed the first fluorescent peptide biosensor which has been successfully implemented to monitor kinase activity in skin samples and melanoma tumour xenografts. Moreover by enabling to monitor response to CDK4 inhibitors, this biosensor constitutes an attractive companion assay to identify compounds of therapeutic relevance for melanoma.

  10. Apoptosis is an early event during phthalocyanine photodynamic therapy-induced ablation of chemically induced squamous papillomas in mouse skin.

    PubMed

    Agarwal, R; Korman, N J; Mohan, R R; Feyes, D K; Jawed, S; Zaim, M T; Mukhtar, H

    1996-04-01

    Photodynamic therapy (PDT) is a promising new modality to treat malignant neoplasms including superficial skin cancers. In our search for an ideal photosensitizer for PDT, Pc 4, a silicon phthalocyanine, has shown promising results both in in vitro assays and in implanted tumors. In this study we assessed the efficacy of Pc 4 PDT in the ablation of murine skin tumors; and the evidence for apoptosis during tumor ablation was also obtained. The Pc 4 was administered through tail vein injection to SENCAR mice bearing chemically induced squamous papillomas, and 24 h later the lesions were illuminated with an argon ion-pumped dye laser tuned at 675 nm for a total light dose of 135 J/cm2. Within 72-96 h, almost complete tumor shrinkage occurred; no tumor regrowth was observed up to 90 days post-PDT. As evident by nucleosome-size DNA fragmentation, appearance of apoptotic bodies in hematoxylin and eosin staining and direct immunoperoxidase detection of digoxigenin-labeled genomic DNA in sections, apoptosis was clearly evident 6 h post-PDT at which time tumor shrinkage was less than 30%. The apoptotic bodies, as evident by the condensation of chromatin material around the periphery of the nucleus and increased vacuolization of the cytoplasm, were also observed in electron microscopic studies of the tumor tissues following Pc 4 PDT. The extent of apoptosis was greater at 15 h than at 6 and 10 h post-PDT. Taken together, our results clearly show that Pc 4 may be an effective photosensitizer for PDT of nonmelanoma skin cancer, and that apoptosis is an early event during this process.

  11. Photoprotective Potential of Penta-O-Galloyl-β-DGlucose by Targeting NF-κB and MAPK Signaling in UVB Radiation-Induced Human Dermal Fibroblasts and Mouse Skin.

    PubMed

    Kim, Byung-Hak; Choi, Mi Sun; Lee, Hyun Gyu; Lee, Song-Hee; Noh, Kum Hee; Kwon, Sunho; Jeong, Ae Jin; Lee, Haeri; Yi, Eun Hee; Park, Jung Youl; Lee, Jintae; Joo, Eun Young; Ye, Sang-Kyu

    2015-11-01

    Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-κB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage.

  12. Photoprotective Potential of Penta-O-Galloyl-β-DGlucose by Targeting NF-κB and MAPK Signaling in UVB Radiation-Induced Human Dermal Fibroblasts and Mouse Skin

    PubMed Central

    Kim, Byung-Hak; Choi, Mi Sun; Lee, Hyun Gyu; Lee, Song-Hee; Noh, Kum Hee; Kwon, Sunho; Jeong, Ae Jin; Lee, Haeri; Yi, Eun Hee; Park, Jung Youl; Lee, Jintae; Joo, Eun Young; Ye, Sang-Kyu

    2015-01-01

    Exposure of the skin to ultraviolet radiation can cause skin damage with various pathological changes including inflammation. In the present study, we identified the skin-protective activity of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (pentagalloyl glucose, PGG) in ultraviolet B (UVB) radiation-induced human dermal fibroblasts and mouse skin. PGG exhibited antioxidant activity with regard to intracellular reactive oxygen species (ROS) generation as well as ROS and reactive nitrogen species (RNS) scavenging. Furthermore, PGG exhibited anti-inflammatory activity, inhibiting the activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, resulting in inhibition of the expression of pro-inflammatory mediators. Topical application of PGG followed by chronic exposure to UVB radiation in the dorsal skin of hairless mice resulted in a significant decrease in the progression of inflammatory skin damages, leading to inhibited activation of NF-κB signaling and expression of pro-inflammatory mediators. The present study demonstrated that PGG protected from skin damage induced by UVB radiation, and thus, may be a potential candidate for the prevention of environmental stimuli-induced inflammatory skin damage. PMID:26537189

  13. Formation of protoporphyrin IX in mouse skin after topical application of 5-aminolevulinic acid and its methyl esther

    NASA Astrophysics Data System (ADS)

    Sorensen, Roar; Juzenas, Petras; Iani, Vladimir; Moan, Johan

    1999-02-01

    Normal skin of nude mice (Balb/c) was treated topically with 5-aminolevulinic acid (ALA) and its methyl ester (ALA-Me) for 24 hours. Approximately 0.1 gram of freshly prepared cream was applied to a spot of 1 cm2 on the flank of the mice, which was then covered with a transparent dressing. The ALA induced protoporphyrin IX (PpIX) was studied by means of a noninvasive fiber-optic fluorescence probe connected to a luminescence spectrometer. The excitation wavelength was 407 nm, and the emission wavelength was 637 nm. For the first hour a slight lag in PpIX production was observed for the mice treated with ALA-Me compared to the mice treated with ALA. After approximately 12 hours the ALA and the ALA-Me treated mice showed the same PpIX fluorescence intensity. From 12 hours until 24 hours the PpIX fluorescence intensity decreased for both treatment modalities, even though ALA and ALA-Me were continuously present. At 24 hours ALA-Me-treated mice had less than half the amount of PpIX in their skin compared with ALA- treated mice.

  14. Cancer promotion in a mouse-skin model by a 60-Hz magnetic field: II. Tumor development and immune response.

    PubMed

    McLean, J R; Stuchly, M A; Mitchel, R E; Wilkinson, D; Yang, H; Goddard, M; Lecuyer, D W; Schunk, M; Callary, E; Morrison, D

    1991-01-01

    This paper describes preliminary findings on the influence of 60-Hz (2-mT) magnetic fields on tumor promotion and co-promotion in the skins of mice. The effect of magnetic fields on natural killer (NK) cell activity in spleen and blood was also examined. Groups of 32 juvenile female mice were exposed to the magnetic field as described in part I. The dorsal skin of all animals was treated with a subthreshold dose of the carcinogen 7,12-dimethyl-benz(a)anthracene (DMBA). One week after the treatment, two groups were sham exposed (group A) or field exposed at 2 mT (group B) 6 h/day for 21 weeks, to test whether the field would act as a tumor promoter. No tumors developed in these two groups of mice. To test whether the magnetic field would modify tumor development by directly affecting tumor growth or by suppressing immune surveillance, two additional groups of mice were treated weekly with the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (TPA) and then either sham exposed (group C) or field exposed (group D). The time to appearance of tumors was shorter (but not statistically so) in the group exposed to magnetic fields and TPA. Some differences in NK cell activity and spleen size were observed between the sham- and field-exposed groups.

  15. Anti-CD11a ameliorates disease in the human psoriatic skin-SCID mouse transplant model: comparison of antibody to CD11a with Cyclosporin A and clobetasol propionate.

    PubMed

    Zeigler, M; Chi, Y; Tumas, D B; Bodary, S; Tang, H; Varani, J

    2001-09-01

    The present study assesses the applicability of human skin-SCID (severe combined immunodeficiency) mouse chimeras in testing antipsoriatic therapeutics. Three agents were examined: (1) a monoclonal antibody to the alpha subunit of leukocyte function associated antigen-1 integrin (CD11a); (2) Cyclosporin A; and (3) clobetasol propionate (Temovate), a potent topical corticosteroid used clinically in the treatment of psoriasis. Skin transplanted to SCID mice from normal human volunteers or from psoriatic lesional skin was allowed to heal for 3 to 5 weeks before application of test reagents. During this period, psoriatic skin, which was 3.8-fold thicker than the corresponding normal skin before transplantation, maintained its phenotype (ie, increased epidermal thickness, rete ridges with blunted ends, and intralesional presence of T lymphocytes). Transplanted normal human skin, however, underwent a hyperplastic response during this period, resulting in a 2.4-fold increase in epidermal thickness. After the healing period, animals transplanted with normal or psoriatic skin were treated for 14 days by daily intraperitoneal injection of either Cyclosporin A or a monoclonal antibody to human CD11a, or by topical application of clobetasol propionate. At the end of the treatment period, the mice were killed and the tissue evaluated morphometrically for changes in epidermal thickness and immunohistologically for the presence of T lymphocytes. Both Cyclosporin A and anti-CD11a reduced the epidermal thickness of transplanted psoriatic skin, whereas neither reagent significantly reduced the thickness of transplanted normal skin. T lymphocytes were detected in the skin from treated animals; there did not seem to be any reduction in the number of T lymphocytes. Clobetasol propionate reduced the epidermal thickness of both normal and psoriatic skin. These data indicate that, in this model, therapies directed against pathophysiologic mechanisms that contribute to psoriasis can be

  16. Potent Immunity to Low Doses of Influenza Vaccine by Probabilistic Guided Micro-Targeted Skin Delivery in a Mouse Model

    PubMed Central

    Prow, Tarl W.; Crichton, Michael L.; Fairmaid, Emily J.; Roberts, Michael S.; Frazer, Ian H.; Brown, Lorena E.; Kendall, Mark A. F.

    2010-01-01

    Background Over 14 million people die each year from infectious diseases despite extensive vaccine use [1]. The needle and syringe—first invented in 1853—is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe. Methodology/Principal Findings To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch™, which contains an array of densely packed projections (21025/cm2) invisible to the human eye (110 µm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax® 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe—but with less than 1/100th of the delivered antigen. Conclusions/Significance Our results represent a marked improvement—an order of magnitude greater than reported by others—for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies—and we speculate that successful translation of these findings into humans could uniquely assist with

  17. The heparan sulphate deficient Hspg2 exon 3 null mouse displays reduced deposition of TGF-β1 in skin compared to C57BL/6 wild type mice.

    PubMed

    Shu, Cindy; Smith, Susan M; Melrose, James

    2016-06-01

    This was an observational study where we examined the role of perlecan HS on the deposition of TGF-β1 in C57BL/6 and Hspg2(∆3-/∆3-) perlecan exon 3 null mouse skin. Despite its obvious importance in skin repair and tissue homeostasis no definitive studies have immunolocalised TGF-β1 in skin in WT or Hspg2(∆3-/∆3-) perlecan exon 3 null mice. Vertical parasagittal murine dorsal skin from 3, 6 and 12 week old C57BL/6 and Hspg2(∆3-/∆3-) mice were fixed in neutral buffered formalin, paraffin embedded and 4 μm sections stained with Mayers haematoxylin and eosin (H & E). TGF-β1 was immunolocalised using a rabbit polyclonal antibody, heat retrieval and the Envision NovaRED detection system. Immunolocalisation of TGF-β1 differed markedly in C57BL/6 and Hspg2(∆3-/∆3-) mouse skin, ablation of exon 3 of Hspg2 resulted in a very severe reduction in the deposition of TGF-β1 in skin 3-12 weeks postnatally. The reduced deposition of TGF-β1 observed in the present study would be expected to impact detrimentally on the remodelling and healing capacity of skin in mutant mice compounding on the poor wound-healing properties already reported for perlecan exon 3 null mice due to an inability to signal with FGF-2 and promote angiogenic repair processes. TGF-β1 also has cell mediated effects in tissue homeostasis and matrix stabilisation a reduction in TGF-β1 deposition would therefore be expected to detrimentally impact on skin homeostasis in the perlecan mutant mice.

  18. Response of mouse skin to tattooing: use of SKH-1 mice as a surrogate model for human tattooing

    SciTech Connect

    Gopee, Neera V.; Cui, Yanyan; Olson, Greg; Warbritton, Alan R.; Miller, Barbara J.; Couch, Letha H.; Wamer, Wayne G.; Howard, Paul C. . E-mail: PHoward@nctr.fda.gov

    2005-12-01

    Tattooing is a popular cosmetic practice involving more than 45 million US citizens. Since the toxicology of tattoo inks and pigments used to formulate tattoo inks has not been reported, we studied the immunological impact of tattooing and determined recovery time from this trauma. SKH-1 hairless mice were tattooed using commercial tattoo inks or suspensions of titanium dioxide, cadmium sulfide, or iron oxide, and sacrificed at 0.5, 1, 3, 4, 7, or 14 days post-tattooing. Histological evaluation revealed dermal hemorrhage at 0.5 and 1 day. Acute inflammation and epidermal necrosis were initiated at 0.5 day decreasing in incidence by day 14. Dermal necrosis and epidermal hyperplasia were prominent by day 3, reducing in severity by day 14. Chronic active inflammation persisted in all tattooed mice from day 3 to 14 post-tattooing. Inguinal and axillary lymph nodes were pigmented, the inguinal being most reactive as evidenced by lymphoid hyperplasia and polymorphonuclear infiltration. Cutaneous nuclear protein concentrations of nuclear factor-kappa B were elevated between 0.5 and 4 days. Inflammatory and proliferative biomarkers, cyclooxygenase-1, cyclooxygenase-2, and ornithine decarboxylase protein levels were elevated between 0.5 and 4 days in the skin and decreased to control levels by day 14. Interleukin-1 beta and interleukin-10 were elevated in the lymph nodes but suppressed in the tattooed skin, with maximal suppression occurring between days 0.5 and 4. These data demonstrate that mice substantially recover from the tattooing insult by 14 days, leaving behind pigment in the dermis and the regional lymph nodes. The response seen in mice is similar to acute injury seen in humans, suggesting that the murine model might be a suitable surrogate for investigating the toxicological and phototoxicological properties of ingredients used in tattooing.

  19. The Prostaglandin E2 Receptor, EP2, Stimulates Keratinocyte Proliferation in Mouse Skin by G Protein-dependent and β-Arrestin1-dependent Signaling Pathways*

    PubMed Central

    Chun, Kyung-Soo; Lao, Huei-Chen; Langenbach, Robert

    2010-01-01

    The prostaglandin E2 (PGE2) G protein-coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun, K. S., Lao, H. C., Trempus, C. S., Okada, M., and Langenbach, R. (2009) Carcinogenesis 30, 1620–1627). Because keratinocyte proliferation is essential for skin tumor development, EP2-mediated signaling pathways that contribute to keratinocyte proliferation were investigated. A single topical application of the EP2 agonist, butaprost, dose-dependently increased keratinocyte replication via activation of epidermal growth factor receptor (EGFR) and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR-β-arrestin-Src signaling complex, the possibility of a β-arrestin1-Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced β-arrestin1-Src complex formation and increased both Src and EGFR activation. A role for β-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that β-arrestin1 deficiency significantly reduced Src and EGFR activation. In agreement with a β-arrestin1-Src complex contributing to EGFR activation, Src and EGFR inhibition (PP2 and AG1478, respectively) indicated that Src was upstream of EGFR. Butaprost also induced the activation of Akt, ERK1/2, and STAT3, and both β-arrestin1 deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to β-arrestin1-dependent EGFR activation, butaprost increased PKA activation, as measured by phospho-GSK3β (p-GSK3β) and p-cAMP-response element-binding protein formation. PKA inhibition (H89 or RP-adenosine-3′,5′-cyclic monophosphorothioate (RP-cAMPS)) decreased butaprost-induced cAMP-response element-binding protein and ERK activation but did not affect EGFR activation, whereas β-arrestin1 deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation, thus indicating that they were independent EP2

  20. The prostaglandin E2 receptor, EP2, stimulates keratinocyte proliferation in mouse skin by G protein-dependent and {beta}-arrestin1-dependent signaling pathways.

    PubMed

    Chun, Kyung-Soo; Lao, Huei-Chen; Langenbach, Robert

    2010-12-17

    The prostaglandin E(2) (PGE(2)) G protein-coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun, K. S., Lao, H. C., Trempus, C. S., Okada, M., and Langenbach, R. (2009) Carcinogenesis 30, 1620-1627). Because keratinocyte proliferation is essential for skin tumor development, EP2-mediated signaling pathways that contribute to keratinocyte proliferation were investigated. A single topical application of the EP2 agonist, butaprost, dose-dependently increased keratinocyte replication via activation of epidermal growth factor receptor (EGFR) and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR-β-arrestin-Src signaling complex, the possibility of a β-arrestin1-Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced β-arrestin1-Src complex formation and increased both Src and EGFR activation. A role for β-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that β-arrestin1 deficiency significantly reduced Src and EGFR activation. In agreement with a β-arrestin1-Src complex contributing to EGFR activation, Src and EGFR inhibition (PP2 and AG1478, respectively) indicated that Src was upstream of EGFR. Butaprost also induced the activation of Akt, ERK1/2, and STAT3, and both β-arrestin1 deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to β-arrestin1-dependent EGFR activation, butaprost increased PKA activation, as measured by phospho-GSK3β (p-GSK3β) and p-cAMP-response element-binding protein formation. PKA inhibition (H89 or R(P)-adenosine-3',5'-cyclic monophosphorothioate (R(P)-cAMPS)) decreased butaprost-induced cAMP-response element-binding protein and ERK activation but did not affect EGFR activation, whereas β-arrestin1 deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation, thus indicating that they were independent EP2

  1. Silibinin prevents ultraviolet B radiation-induced epidermal damages in JB6 cells and mouse skin in a p53-GADD45α-dependent manner.

    PubMed

    Roy, Srirupa; Deep, Gagan; Agarwal, Chapla; Agarwal, Rajesh

    2012-03-01

    Better preventive strategies are required to reduce ultraviolet (UV)-caused photodamage, the primary etiological factor for non-melanoma skin cancer (NMSC). Accordingly, here we examined the preventive efficacy of silibinin against UVB-induced photodamage using mouse epidermal JB6 cells and SKH1 hairless mouse epidermis. In JB6 cells, silibinin pretreatment protected against apoptosis and accelerated the repair of cyclobutane pyrimidine dimers (CPD) induced by moderate dose of UVB (50 mJ/cm(2)), which we are at risk of daily exposure. Silibinin also reversed UVB-induced S phase arrest, reducing both active DNA synthesizing and inactive S phase populations. In mechanistic studies, UVB-irradiated cells showed a transient upregulation of both phosphorylated (Ser-15 and Ser-392) and total p53, whereas silibinin pretreatment led to a more sustained upregulation and stronger nuclear localization of p53. Silibinin also caused a marked upregulation of GADD45α, a downstream target of p53, implicated in DNA repair and cell cycle regulation. Importantly, under p53 and GADD45α knockdown conditions, cells were more susceptible to UVB-induced apoptosis without any significant S phase arrest, and protective effects of silibinin were compromised. Similar to the in vitro results, topical application of silibinin prior to or immediately after UVB irradiation resulted in sustained increase in p53 and GADD45α levels and accelerated CPD removal in the epidermis of SKH1 hairless mice. Together, our results show for the first time that p53-mediated GADD45α upregulation is the key mechanism by which silibinin protects against UVB-induced photodamage and provides a strong rationale to investigate silibinin in reducing the risk and/or preventing early onset of NMSC.

  2. Epidermal YAP2-5SA-ΔC Drives β-Catenin Activation to Promote Keratinocyte Proliferation in Mouse Skin In Vivo.

    PubMed

    Akladios, Bassem; Mendoza-Reinoso, Veronica; Samuel, Michael S; Hardeman, Edna C; Khosrotehrani, Kiarash; Key, Brian; Beverdam, Annemiek

    2017-03-01

    The epidermis is a highly regenerative tissue. YAP is a pivotal regulator of stem/progenitor cells in tissue regeneration, including in the epidermis. The molecular mechanisms downstream of YAP that activate epidermal cell proliferation remain largely unknown. We found that YAP and β-catenin co-localize in the nuclei of keratinocytes in the regenerating epidermis in vivo and in proliferating HaCaT keratinocytes in vitro. Inactivation of YAP in HaCaT keratinocytes resulted in reduced activated β-catenin and reduced keratinocyte numbers in vitro. In addition, we found that in the hyperplastic epidermis of YAP2-5SA-ΔC mice, the mutant YAP2-5SA-ΔC protein was predominantly localized in the keratinocyte nuclei and caused increased expression of activated nuclear β-catenin. Accordingly, β-catenin transcriptional activity was elevated in the skin of live YAP2-5SA-ΔC/TOPFLASH mice. Lastly, loss of β-catenin in basal keratinocytes of YAP2-5SA-ΔC/K14-creERT/CtnnB1(-/-) mice resulted in reduced proliferation of basal keratinocytes and a striking rescue of the hyperplastic abnormalities. Taken together, our work shows that YAP2-5SA-ΔC drives β-catenin activity to promote basal keratinocyte proliferation in the mouse skin in vivo. Our data shine new light on the etiology of regenerative dermatological disorders and other human diseases that display increased YAP and β-catenin activity.

  3. Phototumorigenesis studies of 5-methoxypsoralen in bergamot oil: evaluation and modification of risk of human use in an albino mouse skin model.

    PubMed

    Young, A R; Walker, S L; Kinley, J S; Plastow, S R; Averbeck, D; Morlière, P; Dubertret, L

    1990-11-01

    The skin of the female hairless albino mouse (Skh 1) was used to study the enhancement of solar simulated radiation (SSR) tumorigenesis by 5-methoxypsoralen (5-MOP) in model perfumes that contain bergamot oil. This work was done in association with yeast mutagenicity studies and human skin phototoxicity studies. Analyses of time-to-onset of tumour observation with 5-MOP at 0, 5, 15 and 50 ppm show a highly significant 5-MOP dose effect and the data indicate that 5-MOP has phototumorigenic potential even at 5 ppm. The addition of 0.5% UVB and 0.5% UVA sunscreens significantly reduces the tumorigenicity associated with the vehicle (i.e. 5-MOP at 0 ppm) and 5-MOP at all concentrations. Pairwise comparisons of 5-MOP (at 5 or 15 ppm) plus sunscreens with vehicle plus sunscreens show that the sunscreens afford total protection at the lower 5-MOP concentrations. Additional studies show that a 5-6 h delay between 5-MOP application and SSR exposure defers the time-to-onset of tumours as does intermittent 5-MOP and SSR treatment. A comparison of 5-MOP at 50 ppm in bergamot oil with 5-MOP at 50 ppm prepared from pure 5-MOP crystals shows identical results, indicating that the active phototumorigenic agent in bergamot oil is 5-MOP and not other related compounds, which may be present at greater concentrations. Analyses of tumour histology at death show, in general, similar patterns of malignancy for all groups. Thus although it is possible to delay tumorigenesis by various strategies, the tumours that eventually develop are just as likely to be malignant, if not more so, when compared with non-delayed groups.

  4. Vitamin D for combination photodynamic therapy of skin cancer in individuals with vitamin D deficiency: Insights from a preclinical study in a mouse model of squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Sanjay; Thomas, Erik; Hasan, Tayyaba; Maytin, Edward V.

    2016-03-01

    Combination photodynamic therapy (cPDT) in which vitamin D (VD) is given prior to aminolevulinate, a precursor (pro-drug) for protoporphyrin IX (PpIX), is an approach developed in our laboratory. We previously showed that 1α,25- dihydroxyvitamin D3 (calcitriol), given prior to PDT, enhances accumulation of PpIX and improves cell death post-PDT in a mouse skin cancer model. However, since calcitriol poses a risk for hypercalcemia, we replaced systemic calcitriol with oral cholecalciferol (D3), administered as a high (tenfold, "10K") diet over a ten-day period. Here, we ask whether VD deficiency might alter the response to cPDT. Nude mice were fed a VD-deficient diet for at least 4 weeks ("deficient"); controls were fed a normal 1,000 IU/kg diet ("1K"). Human A431 cells were implanted subcutaneously and mice were switched to the 10K diet or continued on their baseline diets (controls). In other experiments, mice received a human equivalent dose of 50,000 IU D3 by oral gavage, to simulate administration of a single, high-dose VD pill. At various times, tumors were harvested and serum was collected to measure levels of VD metabolic intermediates. A significant increase in PpIX levels and in the expression of differentiation and proliferation markers in tumor tissue was observed after VD supplementation of both the deficient and 1K mice. Further results describing mechanistic details of PpIX enhancement through alteration of heme- and VD-metabolic enzyme levels will be presented. Based on these results, a clinical study using oral vitamin D prior to PDT for human skin cancer should be performed.

  5. Polycyclic aromatic hydrocarbons as skin carcinogens: comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse.

    PubMed

    Siddens, Lisbeth K; Larkin, Andrew; Krueger, Sharon K; Bradfield, Christopher A; Waters, Katrina M; Tilton, Susan C; Pereira, Cliff B; Löhr, Christiane V; Arlt, Volker M; Phillips, David H; Williams, David E; Baird, William M

    2012-11-01

    The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response with mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by ³²P post-labeling, did not correlate with tumor incidence. PAH-dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and phase 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs).

  6. The effect of dimethylsulfoxide, 1-[2-(decylthio)ethyl]azacyclopentan-2-one and Labrafac(®)CC on porphyrin formation in normal mouse skin during topical application of methyl 5-aminolevulinate: A fluorescence and extraction study.

    PubMed

    Bugaj, Andrzej; Iani, Vladimir; Juzeniene, Asta; Juzenas, Petras; Ma, Li-Wei; Moan, Johan

    2006-03-01

    In this work, the effect of 10% of dimethylsulfoxide (DMSO), 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101) and Labrafac(®)CC (a mixture of caprylic and capric acid triglycerides) on porphyrin formation in mouse skin during topical application of methyl 5-aminolevulinate (MAL) was studied. The porphyrin level in mouse skin was determined by measuring directly fluorescence and by extraction method. The porphyrin fluorescence kinetics during continuous application of MAL in creams in concentrations 2, 10 and 20% (wt./wt.) for up to 7h showed that in this concentration range the kinetics of porphyrin production in the site of application does not depend significantly on the MAL concentration. After 24h of application of all studied creams the porphyrin fluorescence in the area of treatment was dramatically reduced to be about two-fold higher than the skin autofluorescence, suggesting a significant decrease of the porphyrin concentration in these sites, although in all cases traces of porphyrins were found. It was found by extraction method that a 10% MAL cream with 10% DMSO for 4h increased the concentration of porphyrin about four-fold compared with 10% MAL cream alone. The presence of 10% HPE-101 or 10% Labrafac(®)CC in the 10% MAL cream increased the porphyrin concentration in the area of application about 2.5- and 2-fold, respectively, as compared with MAL cream without enhancers. No statistically significant difference was found between the effects of the creams containing 10% MAL with 10% HPE-101 or 10% Labrafac(®)CC. The results obtained after 24h of mouse skin treatment with the same creams showed a large decrease of porphyrin formation in comparison with results found after 4h. All porphyrin concentrations measured after this time of MAL creams application were similar. Skin erythema was observed using MAL cream with DMSO and HPE-101, but not with Labrafac(®)CC. Our work suggests that the new penetration enhancer Labrafac(®)CC in creams with MAL

  7. Ischemic Tissue Injury in the Dorsal Skinfold Chamber of the Mouse: A Skin Flap Model to Investigate Acute Persistent Ischemia

    PubMed Central

    Harder, Yves; Schmauss, Daniel; Wettstein, Reto; Egaña, José T.; Weiss, Fabian; Weinzierl, Andrea; Schuldt, Anna; Machens, Hans-Günther; Menger, Michael D.; Rezaeian, Farid

    2014-01-01

    Despite profound expertise and advanced surgical techniques, ischemia-induced complications ranging from wound breakdown to extensive tissue necrosis are still occurring, particularly in reconstructive flap surgery. Multiple experimental flap models have been developed to analyze underlying causes and mechanisms and to investigate treatment strategies to prevent ischemic complications. The limiting factor of most models is the lacking possibility to directly and repetitively visualize microvascular architecture and hemodynamics. The goal of the protocol was to present a well-established mouse model affiliating these before mentioned lacking elements. Harder et al. have developed a model of a musculocutaneous flap with a random perfusion pattern that undergoes acute persistent ischemia and results in ~50% necrosis after 10 days if kept untreated. With the aid of intravital epi-fluorescence microscopy, this chamber model allows repetitive visualization of morphology and hemodynamics in different regions of interest over time. Associated processes such as apoptosis, inflammation, microvascular leakage and angiogenesis can be investigated and correlated to immunohistochemical and molecular protein assays. To date, the model has proven feasibility and reproducibility in several published experimental studies investigating the effect of pre-, peri- and postconditioning of ischemically challenged tissue. PMID:25489743

  8. Mouse skin tumor initiation-promotion and complete carcinogenesis bioassays: mechanisms and biological activities of emission samples.

    PubMed Central

    Nesnow, S; Triplett, L L; Slaga, T J

    1983-01-01

    Extracts of soots obtained from various sources were applied to the skin of mice in an effort to identify carcinogens in these mixtures and to link these materials to the etiology of human cancer. Samples of coal chimney soot, coke oven materials, industrial carbon black, oil shale soot, and gasoline vehicle exhaust materials have been examined by this method. The studies reported here have been constructed to compare the carcinogenic and tumorigenic potency of extracts from various particulate emissions: coke ovens, diesel and gasoline vehicles and a roofing tar pot. Automobile emission samples were obtained by collecting the diluted and cooled exhaust on Teflon-coated glass fiber filters. Coke oven and roofing tar samples were particulate emission samples collected by impaction and filtration. The organic components associated with each of the particles were extracted with dichloromethane and dermally applied to SENCAR mice. All agents were applied as tumor initiators by using a five-dose protocol. Selected extracts were also applied as complete carcinogens and as tumor promotors. Statistical analyses of the resulting tumor data were performed by using nonlinear Poisson and probit models. The results from these experiments provide a suitable data base for comparative potency estimation of complex mixtures. PMID:6825618

  9. Penetration enhancement in mouse skin and lipolysis in adipocytes by TAT-GKH, a new cosmetic ingredient.

    PubMed

    Lim, Jun Man; Chang, Min Youl; Park, Sun Gyoo; Kang, Nae Gyu; Song, Young Sook; Lee, Young Hwa; Yoo, Young Chang; Cho, Wan Goo; Choi, Soo Young; Kang, She Hoon

    2003-01-01

    Since the basic domain of human immunodeficiency virus type I (HIV-1) transactivator of transcription (TAT) protein was reported to possess the ability to traverse biological membranes efficiently, various therapeutic proteins have been attached to TAT for the purpose of therapy. In this study, the tripeptide GKH (glycine-lysine-histidine) derived from parathyroid hormone (PTH), known as lipolytic peptide, was attached to 9-poly lysine (TAT) to be used as a cosmetic ingredient in slimming products. TAT-GKH at 10(-5) M induced approximately 37.6% and 41.5% maximal lipolytic effects in cultured 3T3-L1 differentiated adipocytes and in epididymal adipocytes isolated from rats, respectively, compared with basal lipolysis. The lipolytic effect of GKH was not changed by TAT-GKH fusion. In cytotoxicity tests, there was no cytotoxicity in any dose concentration of TAT-GKH. We confirmed that TAT-GKH induced lipolytic activity by GKH without cytotoxicity and with the possibility of its use as a safe cosmetic ingredient. TAT-GKH elevated penetration into excised hairless mice skin 36 times more efficiently than GKH. TAT-GKH can be used as a cosmetic ingredient in slimming products, with both penetration enhancement and lipolytic effect without cytotoxicity.

  10. Fractionation of a tumor-initiating UV dose introduces DNA damage-retaining cells in hairless mouse skin and renders subsequent TPA-promoted tumors non-regressing

    PubMed Central

    van de Glind, Gerline; Rebel, Heggert; van Kempen, Marika; Tensen, Kees; de Gruijl, Frank

    2016-01-01

    Sunburns and especially sub-sunburn chronic UV exposure are associated with increased risk of squamous cell carcinomas (SCCs). Here we focus on a possible difference in tumor initiation from a single severe-sunburn dose (on day 1, 21 hairless mice) and from an equal dose fractionated into very low sub-sunburn doses not causing any (growth-promoting) epidermal hyperplasia (40 days daily exposure, n=20). From day 47 all mice received 12-O-Tetradecanoylphorbol-13-acetate (TPA) applications (2x/wk) for 20 weeks to promote tumor development within the lifetime of the animals. After the sub-sunburn regimen sparse DNA damage-retaining basal cells (quiescent stem cells, QSCs) remained in the non-hyperplastic epidermis. These cells were forced to divide by TPA. After discontinuation of TPA tumors regressed and disappeared in the ‘sunburn group’ but persisted and grew in the ‘sub-sunburn group’ (0.06 vs 2.50 SCCs and precursors ≥4mm/mouse after 280 days, p=0.03). As the tumors carried no mutations in p53, H/K/N-Ras and Notch1/2, these ‘usual suspects' were not involved in the UV-driven tumor initiation. Although we could not selectively eliminate QSCs (unknown phenotype) to establish causality, our data suggest that forcing specifically DNA damage-retaining QSCs to divide – with high mutagenic risk - gives rise to persisting (mainly ‘in situ’) skin carcinomas. PMID:26797757

  11. Relation between speckle decorrelation and optical phase conjugation (OPC)-based turbidity suppression through dynamic scattering media: a study on in vivo mouse skin

    PubMed Central

    Jang, Mooseok; Ruan, Haowen; Vellekoop, Ivo M.; Judkewitz, Benjamin; Chung, Euiheon; Yang, Changhuei

    2014-01-01

    Light scattering in biological tissue significantly limits the accessible depth for localized optical interrogation and deep-tissue optical imaging. This challenge can be overcome by exploiting the time-reversal property of optical phase conjugation (OPC) to reverse multiple scattering events or suppress turbidity. However, in living tissue, scatterers are highly movable and the movement can disrupt time-reversal symmetry when there is a latency in the OPC playback. In this paper, we show that the motion-induced degradation of the OPC turbidity-suppression effect through a dynamic scattering medium shares the same decorrelation time constant as that determined from speckle intensity autocorrelation – a popular conventional measure of scatterer movement. We investigated this decorrelation characteristic time through a 1.5-mm-thick dorsal skin flap of a living mouse and found that it ranges from 50 ms to 2.5 s depending on the level of immobilization. This study provides information on relevant time scales for applying OPC to living tissues. PMID:25657876

  12. Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator.

    PubMed

    Viaje, A; Slaga, T J; Wigler, M; Weinstein, I B

    1977-05-01

    The antinflammatory ateroids fluocinoine acetonide, fluocinonide, and fluclorolone acetonide were found to be very effectiveinhibitory agents of mouse skin tumor promotion. These steroids also drastically inhibited epidermal DNA synthesis and epidermal cellular proliferation induced by a phorbal ester tumor promoter. In addition, these compounds were potent inhibitors, of plasminogen activator production in tumor cell cultures. The clinically used non-steroidal antiinflammatory agents oxyphenbutazone, indomethacin, and Seclazone also inhibite tumor promotion but were much less effective. Although these agents are useful against inflammatory disorders in general when given p.o., in our studies they had little effect on inflammation and epidermal cellular proliferation induced by a phorbol ester tumor promoter when given topically. The afore mentioned nonsteroidal antiinflammatory agents also had little effect on epidermal DNA synthesis. Oxyphenbutazone and indomethacin were less potent inhibitors of plasminogen activator production in tumor cells than were the antiinflammatory steroids, and Seclazone produced a negligible inhibition. There is, therefore, a general correlation in the potencies of a series of steroidal antiinflammatory agents for inhibition of tumor promotion and their ability to inhibit plasminogen activator production by tumor cell cultures and epidermal DNA synthesis.

  13. Induction of terminal differentiation-resistant epidermal cells in mouse skin and in papillomas by different initiators during two-stage carcinogenesis.

    PubMed

    Miller, D R; Viaje, A; Rotstein, J; Aldaz, C M; Conti, C J; Slaga, T J

    1989-01-15

    Carcinogen treatment of normal mouse epidermal cells causes some cells, if cultured under the appropriate conditions, to continue to proliferate instead of terminally differentiate, forming foci at 37 degrees C in medium with a calcium level above 0.1 mM. We have examined these Calcium (Ca)-resistant cells formed in the skin of SENCAR mice after treatment with the carcinogen initiator 7,12-dimethylbenz[a]anthracene (DMBA) followed by tumor promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Although in our previous studies TPA promotion initially increased the size but reduced the number of foci caused by the carcinogen initiator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), TPA promotion of DMBA-treated mice increased the size but had no effect on the number of foci. Papillomas resulting from DMBA plus TPA treatment contained many rapidly growing Ca-resistant cells, corroborating our earlier results with MNNG. Permanent cell lines prepared from papilloma-derived foci formed squamous cell carcinomas in nude mice after relatively short periods in culture. These data provide further evidence that Ca-resistant cells may be papilloma (and perhaps carcinoma) precursors in vivo. In addition, since TPA tends to reduce the number of early Ca-resistant cells caused by MNNG but not by DMBA, this may at least partially explain why treatment with DMBA plus TPA is much more effective in producing papillomas in SENCAR mice than is treatment with MNNG plus TPA.

  14. The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin.

    PubMed

    Banki, E; Hajna, Zs; Kemeny, A; Botz, B; Nagy, P; Bolcskei, K; Toth, G; Reglodi, D; Helyes, Zs

    2014-10-01

    We have earlier shown that PACAP-38 decreases neurogenic inflammation. However, there were no data on its receptorial mechanism and the involvement of its PAC1 and VPAC1/2 receptors (PAC1R, VPAC1/2R) in this inhibitory effect. Neurogenic inflammation in the mouse ear was induced by topical application of the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor activator mustard oil (MO). Consequent neurogenic edema, vasodilation and plasma leakage were assessed by measuring ear thickness with engineer's micrometer, detecting tissue perfusion by laser Doppler scanning and Evans blue or indocyanine green extravasation by intravital videomicroscopy or fluorescence imaging, respectively. Myeloperoxidase activity, an indicator of neutrophil infiltration, was measured from the ear homogenates with spectrophotometry. The selective PAC1R agonist maxadilan, the VPAC1/2R agonist vasoactive intestinal polypeptide (VIP) or the vehicle were administered i.p. 15 min before MO. Substance P (SP) concentration of the ear was assessed by radioimmunoassay. Maxadilan significantly diminished MO-induced neurogenic edema, increase of vascular permeability and vasodilation. These inhibitory effects of maxadilan may be partially due to the decreased substance P (SP) levels. In contrast, inhibitory effect of VIP on ear swelling was moderate, without any effect on MO-induced plasma leakage or SP release, however, activation of VPAC1/2R inhibited the increased microcirculation caused by the early arteriolar vasodilation. Neither the PAC1R, nor the VPAC1/2R agonist influenced the MO-evoked increase in tissue myeloperoxidase activity. These results clearly show that PAC1R activation inhibits acute neurogenic arterial vasodilation and plasma protein leakage from the venules, while VPAC1/2R stimulation is only involved in the attenuation of vasodilation.

  15. Bromelain nanoparticles protect against 7,12-dimethylbenz[a]anthracene induced skin carcinogenesis in mouse model.

    PubMed

    Bhatnagar, Priyanka; Pant, Aditya B; Shukla, Yogeshwer; Chaudhari, Bhushan; Kumar, Pradeep; Gupta, Kailash C

    2015-04-01

    Conventional cancer chemotherapy leads to severe side effects, which limits its use. Nanoparticles (NPs) based delivery systems offer an effective alternative. Several evidences highlight the importance of Bromelain (BL), a proteolytic enzyme, as an anti-tumor agent which however has been limited due to the requirement of high doses at the tumor site. Therefore, we illustrate the development of BL loaded poly (lactic-co-glycolic acid) NPs that show enhanced anti-tumor effects compared to free BL. The formulated NPs with a mean particle size of 130.4 ± 8.81 nm exhibited sustained release of BL. Subsequent investigation revealed enhanced anti-tumor ability of NPs in 2-stage skin tumorigenesis mice model. Reduction in average number of tumors (∼ 2.3 folds), delay in tumorigenesis (∼ 2 weeks), percent tumorigenesis (∼ 4 folds), and percent mortality rate as well as a reduction in the average tumor volume (∼ 2.5 folds) in mice as compared to free BL were observed. The NPs were found to be superior in exerting chemopreventive effects over chemotherapeutic effects at 10 fold reduced dose than free BL, validated by the enhanced ability of NPs (∼ 1.8 folds) to protect the DNA from induced damage. The effects were also supported by histopathological evaluations. NPs were also capable of modulating the expression of pro-apoptotic (P53, Bax) and anti-apoptotic (Bcl2) proteins. Therefore, our findings demonstrate that developed NPs formulation could be used to improve the efficacy of chemotherapy by exerting chemo-preventive effects against induced carcinogenesis at lower dosages.

  16. RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model.

    PubMed

    Brady, Rebecca A; Bruno, Vincent M; Burns, Drusilla L

    2015-01-01

    Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of

  17. RNA-Seq Analysis of the Host Response to Staphylococcus aureus Skin and Soft Tissue Infection in a Mouse Model

    PubMed Central

    Brady, Rebecca A.; Bruno, Vincent M.; Burns, Drusilla L.

    2015-01-01

    Staphylococcus aureus is a leading cause of skin and soft tissue infections (SSTI), which are primarily self-limiting. We conducted a comprehensive analysis of the host transcriptome during a S. aureus SSTI to provide insight on the protective mechanisms that thwart these infections. We utilized a murine SSTI model in which one ear is epicutaneously challenged while the other is not. We then harvested these infected and uninfected ears, as well as ears from naïve mice, at one, four, and seven days post-challenge, and performed RNA sequencing (RNA-seq) using the Illumina platform. RNA-seq data demonstrated a robust response at the site of infection. Comparison of gene expression profiles between infected ears and the non-infected ears of challenged mice defined the local response to infection, while comparisons of expression profiles of non-infected ears from challenged mice to ears of naïve mice revealed changes in gene expression levels away from the site indicative of a systemic response. Over 1000 genes exhibited increased expression locally at all tested time points. The local response was more robust than the systemic response. Through evaluation of the RNA-seq data using the Upstream Regulator Analytic as part of the Ingenuity Pathway Analysis software package, we found that changes in the activation and inhibition of regulatory pathways happen first locally, and lag behind systemically. The activated pathways are highly similar at all three time points during SSTI, suggesting a stable global response over time. Transcript increases and pathway activation involve pro- and anti-inflammatory mediators, chemotaxis, cell signaling, keratins, and TH1/TH17 cytokines. Transcript decreases and pathway inhibition demonstrate that metabolic genes and anti-inflammatory pathways are repressed. These data provide insight on the host responses that may aid in resolution of this self-limited S. aureus infection, and may shed light on potential immune correlates of

  18. Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide.

    PubMed

    Black, Adrienne T; Hayden, Patrick J; Casillas, Robert P; Heck, Diane E; Gerecke, Donald R; Sinko, Patrick J; Laskin, Debra L; Laskin, Jeffrey D

    2011-06-01

    Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT™). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000μM) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-β-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.

  19. Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    SciTech Connect

    Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2011-06-01

    Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT{sup TM}). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000 {mu}M) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-{beta}-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.

  20. Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    PubMed Central

    Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2012-01-01

    Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FTTM). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100–1000 µM) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-β-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity. PMID:21457723

  1. Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis

    PubMed Central

    Arabzadeh, Azadeh; Troy, Tammy-Claire; Turksen, Kursad

    2007-01-01

    all the living layers of the epidermis) remained restricted to the cell membrane throughout the tumorigenesis protocol. However commencing 2 weeks after treatment there was a marked decrease in the number of Cldn1-positive basal cells, and the zone of Cldn1-null epidermal cells was expanded up into the lower stratified epidermis throughout the progression of DMBA/TPA treatment. In addition, there was no Cldn1 localization in the infiltrating epidermal structures of the tumorigenic epidermis. Conclusion This is the first demonstration of the changes in Cldn expression in the progression of DMBA/TPA-induced skin tumors; however further investigation into the molecular mechanisms regulating the observed changes in barrier selectivity during tumorigenesis is required. PMID:17945025

  2. Photodynamic therapy using a novel irradiation source, LED lamp, is similarly effective to photodynamic therapy using diode laser or metal-halide lamp on DMBA- and TPA-induced mouse skin papillomas.

    PubMed

    Takahashi, Hidetoshi; Nakajima, Susumu; Ogasawara, Koji; Asano, Ryuji; Nakae, Yoshinori; Sakata, Isao; Iizuka, Hajime

    2014-08-01

    Photodynamic therapy (PDT) is useful for superficial skin tumors such as actinic keratosis and Bowen disease. Although PDT is non-surgical and easily-performed treatment modality, irradiation apparatus is large and expensive. Using 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-ο-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin papilloma model, we compared the efficacy of TONS501- and ALA-PDT with a LED lamp, a diode laser lamp or a metal-halide lamp on the skin tumor regression. TONS501-PDT using 660 nm LED lamp showed anti-tumor effect at 1 day following the irradiation and the maximal anti-tumor effect was observed at 3 days following the irradiation. There was no significant difference in the anti-tumor effects among TONS501-PDT using LED, TONS501-PDT using diode laser, and 5-aminolevulinic acid hydrochloride (ALA)-PDT using metal-halide lamp. Potent anti-tumor effect on DMBA- and TPA-induced mouse skin papilloma was observed by TONS501-PDT using 660 nm LED, which might be more useful for clinical applications.

  3. Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides.

    PubMed

    Gill, H S; Kole, P L; Wiley, J C; Li, K M; Higginbotham, S; Rogan, E G; Cavalieri, E L

    1994-11-01

    Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycyclic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mechanisms of activation, (+/)-trans-DB[a,l]P-11,12-dihydrodiol, (+/-)-anti-DB[a,l]PDE and (+/-)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclization of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiolepoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P. Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 1.33 nmol of compound in 100 microliters of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol in 100 microliters acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn-DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3, 7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodiol and show that the two diolepoxides are less tumorigenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

  4. Polycyclic aromatic hydrocarbons as skin carcinogens: Comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse

    SciTech Connect

    Siddens, Lisbeth K.; Larkin, Andrew; Krueger, Sharon K.; Bradfield, Christopher A.; Waters, Katrina M.; Tilton, Susan C.; Pereira, Cliff B.; Löhr, Christiane V.; Arlt, Volker M.; Phillips, David H.; Williams, David E.; and others

    2012-11-01

    The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4 nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response with mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by {sup 32}P post‐labeling, did not correlate with tumor incidence. PAH‐dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p < 0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and phase 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs). -- Highlights: ► Dibenzo[def,p]chrysene (DBC), 3 PAH mixtures, benzo[a]pyrene (BaP) were compared. ► DBC and 2 PAH mixtures were more potent than Relative Potency Factor estimates. ► Transcriptome profiles 12 hours post initiation were analyzed by microarray. ► Principle components analysis of alterations revealed treatment-based clustering. ► DBC gave a unique

  5. Skin Dictionary

    MedlinePlus

    ... your skin, hair, and nails Skin dictionary Camp Discovery Good Skin Knowledge lesson plans and activities Video library Find a ... your skin, hair, and nails Skin dictionary Camp Discovery Good Skin Knowledge lesson plans and activities Video library Find a ...

  6. Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

    SciTech Connect

    Siddens, Lisbeth K.; Bunde, Kristi L.; Harper, Tod A.; McQuistan, Tammie J.; Löhr, Christiane V.; Bramer, Lisa M.; Waters, Katrina M.; Tilton, Susan C.; Krueger, Sharon K.; and others

    2015-09-01

    FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8 h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4 h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators. - Highlights: • Cyp1b1 null mice exhibit lower skin cancer sensitivity to DBC but not BaP or CTE. • Cyp1b1 expression impacts expression of other PAH metabolizing enzymes. • cis/trans-DBCDE-dA ratio significantly higher in the skin than the spleen, lung or liver • Potency of DBC and CTE in mouse skin is higher than predicted by RPFs.

  7. II. Capsular vaso-mimicry formed by transgenic mammary tumor spheroids implanted ectopically into mouse dorsal skin fold: implications for cellular mechanisms of metastasis.

    PubMed

    Witkiewicz, Halina; Oh, Phil; Schnitzer, Jan E

    2013-01-01

    Most cancer patients die of metastatic disease, not primary tumors, while biological mechanisms leading to metastases remain unclear and effective therapies are missing. Using a mouse dorsal skin chamber model we had observed that tumor growth and vasculature formation could be influenced by the way in vitro cultured (avascular) spheroids of N202 breast tumor cells were implanted; co-implantation of lactating breast tissue created stimulating microenvironment, whereas the absence of the graft resulted in temporary tumor dormancy. This report addressed the issue of cellular mechanisms of the vasculogenic switch that ended the dormancy. In situ ultrastructural analysis revealed that the tumors survived in ectopic microenvironment until some of host and tumor stem cells evolved independently into cells initiating the vasculogenic switch. The tumor cells that survived and proliferated under hypoxic conditions for three weeks were supported by erythrogenic autophagy of others. However, the host microenvironment first responded as it would to non-immunogenic foreign bodies, i.e., by encapsulating the tumor spheroids with collagen-producing fibroblasts. That led to a form of vaso-mimicry consisting of tumor cells amid tumor-derived erythrosomes (synonym of erythrocytes), megakaryocytes and platelets, and encapsulating them all, the host fibroblasts. Such capsular vaso-mimicry could potentially facilitate metastasis by fusing with morphologically similar lymphatic vessels or veins. Once incorporated into the host circulatory system, tumor cells could be carried away passively by blood flow, regardless of their genetic heterogeneity. The fake vascular segment would have permeability properties different from genuine vascular endothelium. The capsular vaso-mimicry was different from vasculogenic mimicry earlier observed in metastases-associated malignant tumors where channels formed by tumor cells were said to contain circulating blood. Structures similar to the vasculogenic

  8. Molybdenum nanoparticles-induced cytotoxicity, oxidative stress, G2/M arrest, and DNA damage in mouse skin fibroblast cells (L929).

    PubMed

    Siddiqui, Maqsood A; Saquib, Quaiser; Ahamed, Maqusood; Farshori, Nida N; Ahmad, Javed; Wahab, Rizwan; Khan, Shams T; Alhadlaq, Hisham A; Musarrat, Javed; Al-Khedhairy, Abdulaziz A; Pant, Aditya B

    2015-01-01

    The present investigation was aimed to study the cytotoxicity, oxidative stress, and genotoxicity induced by molybdenum nanoparticles (Mo-NPs) in mouse skin fibroblast cells (L929). Cells were exposed to different concentrations (1-100 μg/ml) of Mo-NPs (size 40 nm) for 24 and 48 h. After the exposure, different cytotoxicity assays (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide, MTT; neutral red uptake, NRU; and cellular morphology) and oxidative stress markers (lipid peroxidation, LPO; glutathione, GSH; and catalase) were studied. Further, Mo-NPs-induced intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), cell cycle arrest, and DNA damage were also studied. L929 cells treated with Mo-NPs showed a concentration- and time-dependent decrease in cell viability and a loss of the normal cell morphology. The percentage cell viability was recorded as 25%, 42%, and 58% by MTT assay and 24%, 46%, and 56% by NRU assay at 25, 50, and 100 μg/ml of Mo-NPs, respectively after 48 h exposure. Furthermore, the cells showed a significant induction of oxidative stress. This was confirmed by the increase in LPO and ROS generation, as well as the decrease in the GSH and catalase levels. The decrease in MMP also confirms the impaired mitochondrial membrane. The cell cycle analysis and comet assay data revealed that Mo-NPs induced G2/M arrest and DNA damage in a concentration-dependent manner. Our results demonstrated, for the first time, Mo-NPs induced cytotoxicity, oxidative stress and genotoxicity in L929 cells. Thus, data suggest the potential hazardous nature of Mo-NPs.

  9. II. Capsular vaso-mimicry formed by transgenic mammary tumor spheroids implanted ectopically into mouse dorsal skin fold: implications for cellular mechanisms of metastasis

    PubMed Central

    Witkiewicz, Halina

    2013-01-01

    Most cancer patients die of metastatic disease, not primary tumors, while biological mechanisms leading to metastases remain unclear and effective therapies are missing. Using a mouse dorsal skin chamber model we had observed that tumor growth and vasculature formation could be influenced by the way in vitro cultured (avascular) spheroids of N202 breast tumor cells were implanted; co-implantation of lactating breast tissue created stimulating microenvironment, whereas the absence of the graft resulted in temporary tumor dormancy. This report addressed the issue of cellular mechanisms of the vasculogenic switch that ended the dormancy. In situ ultrastructural analysis revealed that the tumors survived in ectopic microenvironment until some of host and tumor stem cells evolved independently into cells initiating the vasculogenic switch. The tumor cells that survived and proliferated under hypoxic conditions for three weeks were supported by erythrogenic autophagy of others. However, the host microenvironment first responded as it would to non-immunogenic foreign bodies, i.e., by encapsulating the tumor spheroids with collagen-producing fibroblasts. That led to a form of vaso-mimicry consisting of tumor cells amid tumor-derived erythrosomes (synonym of erythrocytes), megakaryocytes and platelets, and encapsulating them all, the host fibroblasts. Such capsular vaso-mimicry could potentially facilitate metastasis by fusing with morphologically similar lymphatic vessels or veins. Once incorporated into the host circulatory system, tumor cells could be carried away passively by blood flow, regardless of their genetic heterogeneity. The fake vascular segment would have permeability properties different from genuine vascular endothelium. The capsular vaso-mimicry was different from vasculogenic mimicry earlier observed in metastases-associated malignant tumors where channels formed by tumor cells were said to contain circulating blood. Structures similar to the vasculogenic

  10. Suppression of the metastatic phenotype of a mouse skin carcinoma cell line independent of E-cadherin expression and correlated with reduced Ha-ras oncogene products.

    PubMed

    Caulín, C; López-Barcons, L; Gonzáles-Garrigues, M; Navarro, P; Lozano, E; Rodrigo, I; Gamallo, C; Cano, A; Fabra, A; Quintanilla, M

    1996-02-01

    The HaCa4 cell line, derived from a mouse skin carcinoma induced by Harvey murine sarcoma virus, is highly tumorigenic when injected into nude mice and produces multiple metastases in the lungs. HaCa4 cells express high levels of viral Ha-ras oncogene products, anomalously synthesize the embryonic/simple epithelial keratin K8, and have lost the expression of the cell-cell adhesion receptor E-cadherin (E-CD). E-CD(+) cell clones (E62 and E24), obtained by transfection of an exogenous E-CD cDNA into HaCa4 cells, had a decreased ability to migrate through type IV collagen matrices. However, the E-CD (+) E62 clone remained as metastatic as the parental cell line, whereas the E24 clone, which does not take up the exogenous cDNA but spontaneously switches on the endogenous E-CD gene, suppressed the metastatic phenotype although it maintained its tumorigenicity. E24 cells had fivefold to sixfold lower levels of viral Ha-ras mRNA and p21 protein than the other cell lines. In addition, they did not synthesize K8 but rather switched on keratin K19. The comparison of E-CD proteins synthesized by E62 and E24 cell lines revealed no structural or functional differences because both localized at cell-cell contacts and associated with alpha-catenin, beta-catenin, and plakoglobin. Furthermore, E-CD was still expressed in metastatic lung nodules produced by E62 cells. These results suggest that suppression of the metastatic phenotype in E24 cells occurs independently of E-CD expression and correlates with decreased levels of the oncogenic ras p21 protein.

  11. Both (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxides initiate tumors in mouse skin that possess -CAA- to -CTA- mutations at Codon 61 of c-H-ras.

    PubMed

    Tang, M S; Vulimiri, S V; Viaje, A; Chen, J X; Bilolikar, D S; Morris, R J; Harvey, R G; Slaga, T J; DiGiovanni, J

    2000-10-15

    We have determined the tumor-initiating activity of (+/-)syn- and (+/-)anti-7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide (syn- and anti-DMBADE), the two metabolically formed bay-region diol epoxides of DMBA, and we have also analyzed mutations in the H-ras gene from tumors induced by these compounds. Using a two-stage, initiation-promotion protocol for tumorigenesis in mouse skin, we have found that both syn- and anti-DMBADE are active tumor initiators, and that the occurrence of papillomas is carcinogen dose dependent. All of the papillomas induced by syn-DMBADE (a total of 40 mice), 96% of those induced by anti-DMBADE (a total of 25 mice), and 94% of those induced by DMBA (a total of 16 mice) possessed a -CAA- to -CTA- mutation at codon 61 of H-ras. No mutations in codons 12 or 13 were detected in any tumor. Topical application of syn- and anti-DMBADE produced stable adducts in mouse epidermal DNA, most of which comigrated with stable DNA adducts formed after topical application of DMBA. Further analysis of the data showed that levels of the major syn- and anti-DMBADE-deoxyadenosine adducts formed after topical application of DMBA are sufficient to account for the tumor-initiating activity of this carcinogen on mouse skin. Previously, we showed that both the syn- and anti-DMBADE bind to the adenine (A182) at codon 61 of H-ras. Collectively, these results indicate that the adenine adducts induced by both bay-region diol epoxides of DMBA lead to the mutation at codon 61 of H-ras and, consequently, initiate tumorigenesis in mouse skin.

  12. Skin Diseases: Skin Health and Skin Diseases

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Skin Health and Skin Diseases Past Issues / Fall 2008 Table of Contents ... acne to wrinkles Did you know that your skin is the largest organ of your body? It ...

  13. The prostaglandin receptor EP2 activates multiple signaling pathways and β-arrestin1 complex formation during mouse skin papilloma development

    PubMed Central

    Chun, Kyung-Soo; Lao, Huei-Chen; Trempus, Carol S.; Okada, Manabu; Langenbach, Robert

    2009-01-01

    Prostaglandin E2 (PGE2) is elevated in many tumor types, but PGE2's contributions to tumor growth are largely unknown. To investigate PGE2's roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors—cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2—were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE2 production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3′,5′-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2−/− mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR–β-arrestin–Src complex. Indeed, immunoprecipitation of β-arrestin1 or p-Src indicated the presence of an EP2–β-arrestin1–p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with β-arrestin1 and Src that contributed to signaling and/or EP2

  14. The prostaglandin receptor EP2 activates multiple signaling pathways and beta-arrestin1 complex formation during mouse skin papilloma development.

    PubMed

    Chun, Kyung-Soo; Lao, Huei-Chen; Trempus, Carol S; Okada, Manabu; Langenbach, Robert

    2009-09-01

    Prostaglandin E(2) (PGE(2)) is elevated in many tumor types, but PGE(2)'s contributions to tumor growth are largely unknown. To investigate PGE(2)'s roles, the contributions of one of its receptors, EP2, were studied using the mouse skin initiation/promotion model. Initial studies indicated that protein kinase A (PKA), epidermal growth factor receptor (EGFR) and several effectors-cyclic adenosine 3',5'-monophosphate response element-binding protein (CREB), H-Ras, Src, protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2-were activated in 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted papillomas and that PKA and EGFR inhibition (H89 and AG1478, respectively) decreased papilloma formation. EP2's contributions to the activation of these pathways and papilloma development were determined by inhibiting endogenous TPA-induced PGE(2) production with indomethacin (Indo) and concomitantly treating with the EP2 agonist, CAY10399 (CAY). CAY treatment restored papilloma formation in TPA/Indo-treated mice and increased cyclic adenosine 3',5'-monophosphate and PKA activation as measured by p-CREB formation. CAY treatment also increased EGFR and Src activation and their inhibition by AG1478 and PP2 indicated that Src was upstream of EGFR. CAY also increased H-Ras, ERK1/2 and AKT activation, and AG1478 decreased their activation indicating EGFR being upstream. Supporting EP2's contribution, EP2-/- mice exhibited 65% fewer papillomas and reduced Src, EGFR, H-Ras, AKT and ERK1/2 activation. G protein-coupled receptor (GPCR) activation of EGFR has been reported to involve Src's activation via a GPCR-beta-arrestin-Src complex. Indeed, immunoprecipitation of beta-arrestin1 or p-Src indicated the presence of an EP2-beta-arrestin1-p-Src complex in papillomas. The data indicated that EP2 contributed to tumor formation via activation of PKA and EGFR and that EP2 formed a complex with beta-arrestin1 and Src that contributed to signaling and/or EP2 desensitization.

  15. Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.

    PubMed

    Kiss, Alexi; Koppel, Aaron C; Anders, Joanna; Cataisson, Christophe; Yuspa, Stuart H; Blumenberg, Miroslav; Efimova, Tatiana

    2016-05-01

    p38δ expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38δ in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38δ exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38δ gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38δ is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38δ-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38δ-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-17, and TNFα. Additionally, p38δ-null skin and p38δ-null keratinocytes exhibited increased p38α activation and signaling in response to acute inflammatory challenges, suggesting a role for p38α in stimulating the elevated inflammatory response in p38δ-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38δ(+/+) skin. Altogether, our results indicate that p38δ signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment.

  16. Tattooing of skin results in transportation and light-induced decomposition of tattoo pigments--a first quantification in vivo using a mouse model.

    PubMed

    Engel, Eva; Vasold, Rudolf; Santarelli, Francesco; Maisch, Tim; Gopee, Neera V; Howard, Paul C; Landthaler, Michael; Bäumler, Wolfgang

    2010-01-01

    Millions of people are tattooed with inks that contain azo pigments. The pigments contained in tattoo inks are manufactured for other uses with no established history of safe use in humans and are injected into the skin at high densities (2.5 mg/cm(2)). Tattoo pigments disseminate after tattooing throughout the human body and although some may photodecompose at the injection site by solar or laser light exposure, the extent of transport or photodecomposition under in vivo conditions remains currently unknown. We investigated the transport and photodecomposition of the widely used tattoo Pigment Red 22 (PR 22) following tattooing into SKH-1 mice. The pigment was extracted quantitatively at different times after tattooing. One day after tattooing, the pigment concentration was 186 microg/cm(2) skin. After 42 days, the amount of PR 22 in the skin has decreased by about 32% of the initial value. Exposure of the tattooed skin, 42 days after tattooing, to laser light reduced the amount of PR 22 by about 51% as compared to skin not exposed to laser light. A part of this reduction is as a result of photodecomposition of PR 22 as shown by the detection of corresponding hazardous aromatic amines. Irradiation with solar radiation simulator for 32 days caused a pigment reduction of about 60% and we again assume pigment decomposition in the skin. This study is the first quantitative estimate of the amount of tattoo pigments transported from the skin into the body or decomposed by solar or laser radiation.

  17. Skin Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Skin Cancer What is Skin Cancer? Skin cancer is the most common type ... of approximately 9,480 Americans in 2013. Can Skin Cancer Be Treated? Most basal cell and squamous ...

  18. Enhanced non-peptidergic intraepidermal fiber density and an expanded subset of chloroquine-responsive trigeminal neurons in a mouse model of dry skin itch

    PubMed Central

    Valtcheva, Manouela V.; Samineni, Vijay K.; Golden, Judith P.; Gereau, Robert W.; Davidson, Steve

    2015-01-01

    Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether, followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, CGRP-positive, and GFRα3-positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers, but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of non-peptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons were responsive to the non-histaminergic pruritogen chloroquine after AEW treatment. We conclude that non-peptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus. PMID:25640289

  19. Inhibitory effects of the standardized extract (DA-9601) of Artemisia asiatica Nakai on phorbol ester-induced ornithine decarboxylase activity, papilloma formation, cyclooxygenase-2 expression, inducible nitric oxide synthase expression and nuclear transcription factor kappa B activation in mouse skin.

    PubMed

    Seo, Hyo-Joung; Park, Kwang-Kyun; Han, Seong Su; Chung, Won-Yoon; Son, Mi-Won; Kim, Won-Bae; Surh, Young-Joon

    2002-08-01

    Artemisia asiatica Nakai has been used in traditional Asian medicine for the treatment of inflammatory and other disorders. Previous studies have revealed that the formulated ethanol extract (DA-9601) of A. asiatica has pronounced antioxidative and antiinflammatory activities and exhibits cytoprotective effects against experimentally induced gastrointestinal, hepatic and pancreatic damage. In the present study, we assessed the inhibitory effect of DA-9601 on tumor promotion, which is closely linked to inflammatory tissue damage. As an initial approach to evaluating the possible antitumor-promoting potential of DA-9601, its effects on TPA-induced ear edema were examined in female ICR mice. Pretreatment of the inner surface of the mouse ear with DA-9601 30 min prior to topical application of TPA inhibited ear edema at 5 hr. TPA-stimulated expression of epidermal COX-2 and iNOS was also mitigated by topical application of the same extract. Moreover, DA-9601 abrogated the TPA-mediated activation of NF-kappa B/Rel and AP-1 in mouse epidermis. Suppression of epidermal NF-kappa B by DA-9601 appeared to be mediated in part through inhibition of I kappa B alpha degradation, thereby blocking the nuclear translocation of p65, the functional subunit of NF-kappa B. DA-9601 also significantly suppressed TPA-induced ODC activity and papilloma formation in mouse skin. Taken together, these findings suggest that DA-9601 derived from A. asiatica possesses potential chemopreventive activities.

  20. Antibacterial Evaluation of Synthetic Thiazole Compounds In Vitro and In Vivo in a Methicillin-Resistant Staphylococcus aureus (MRSA) Skin Infection Mouse Model

    PubMed Central

    Mohammad, Haroon; Cushman, Mark; Seleem, Mohamed N.

    2015-01-01

    The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections. PMID:26536129

  1. Engraftment of tonsillar mononuclear cells in human skin/SCID mouse chimera--validation of a novel xenogeneic transplantation model for autoimmune diseases.

    PubMed

    Yamanaka, N; Yamamoto, Y; Kuki, K

    2001-01-01

    Pustulosis palmaris et plantaris (PPP) has been considered as one of the typical tonsillar focal infections, based on the marked clinical improvement of the skin lesions after tonsillectomy. Despite the accumulation of data showing the clinical efficacy of tonsillectomy for this skin lesion, fundamental etiological and pathophysiological issues have yet to be addressed. One primary obstacle hindering investigators has been the lack of an appropriate animal model for this human skin disorder. In the early stage of PPP, it has been reported that lymphocytes, predominantly CD4+ T lymphocytes, infiltrate the palmar and plantar skins. However, the origin and mechanism of infiltration by these lymphocytes is not clear and there are very few reports on whether tonsillar mononuclear cells react directly with the skin. We have been intrigued by the ability to engraft human cells onto severe combined immunodeficiency (SCID) mice, together with the opportunity for long-term graft survival and ability to adoptively transfer various human immunocompetent cells. In this review, we addressed the existing deficiencies in our understanding of the relationship between tonsils and PPP by using emerging transplantation technology involving SCID mice.

  2. Antibacterial Evaluation of Synthetic Thiazole Compounds In Vitro and In Vivo in a Methicillin-Resistant Staphylococcus aureus (MRSA) Skin Infection Mouse Model.

    PubMed

    Mohammad, Haroon; Cushman, Mark; Seleem, Mohamed N

    2015-01-01

    The emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), including strains resistant to current antibiotics, has contributed to an increase in the number of skin infections reported in humans in recent years. New therapeutic options are needed to counter this public health challenge. The aim of the present study was to examine the potential of thiazole compounds synthesized by our research group to be used topically to treat MRSA skin and wound infections. The broth microdilution method confirmed that the lead thiazole compound and four analogues are capable of inhibiting MRSA growth at concentrations as low as 1.3 μg/mL. Additionally, three compounds exhibited a synergistic relationship when combined with the topical antibiotic mupirocin against MRSA in vitro via the checkerboard assay. Thus the thiazole compounds have potential to be used alone or in combination with mupirocin against MRSA. When tested against human keratinocytes, four derivatives of the lead compound demonstrated an improved toxicity profile (were found to be non-toxic up to a concentration of 20 μg/mL). Utilizing a murine skin infection model, we confirmed that the lead compound and three analogues exhibited potent antimicrobial activity in vivo, with similar capability as the antibiotic mupirocin, as they reduced the burden of MRSA present in skin wounds by more than 90%. Taken altogether, the present study provides important evidence that these thiazole compounds warrant further investigation for development as novel topical antimicrobials to treat MRSA skin infections.

  3. Anti-wrinkle effects of Sargassum muticum ethyl acetate fraction on ultraviolet B-irradiated hairless mouse skin and mechanistic evaluation in the human HaCaT keratinocyte cell line

    PubMed Central

    Song, Jae Hyoung; Piao, Mei Jing; Han, Xia; Kang, Kyoung Ah; Kang, Hee Kyoung; Yoon, Weon Jong; Ko, Mi Hee; Lee, Nam Ho; Lee, Mi Young; Chae, Sungwook; Hyun, Jin Won

    2016-01-01

    The present study investigated the photoprotective properties of the ethyl acetate fraction of Sargassum muticum (SME) against ultraviolet B (UVB)-induced skin damage and photoaging in a mouse model. HR-1 strain hairless male mice were divided into three groups: An untreated control group, a UVB-irradiated vehicle group and a UVB-irradiated SME group. The UVB-irradiated mice in the SME group were orally administered with SME (100 mg/kg body weight in 0.1 ml water per day) and then exposed to radiation at a dose of 60–120 mJ/cm2. Wrinkle formation and skin damage were evaluated by analysis of skin replicas, epidermal thickness and collagen fiber integrity in the dermal connective tissue. The mechanism underlying the action of SME was also investigated in the human HaCaT keratinocyte cell line following exposure of the cells to UVB at a dose of 30 mJ/cm2. The protein expression levels and activity of matrix metalloproteinase-1 (MMP-1), and the binding of activator protein-1 (AP-1) to the MMP-1 promoter were assessed in the HaCaT cells using western blot analysis, an MMP-1 fluorescent assay and a chromatin immune-precipitation assay, respectively. The results showed that the mean length and depth of the wrinkles in the UVB-exposed hairless mice were significantly improved by oral administration of SME, which also prevented the increase in epidermal thickness triggered by UVB irradiation. Furthermore, a marked increase in collagen bundle formation was observed in the UVB-treated mice with SME administration. SME pretreatment also significantly inhibited the UVB-induced upregulation in the expression and activity of MMP-1 in the cultured HaCaT keratinocytes, and the UVB-enhanced association of AP-1 with the MMP-1 promoter. These results suggested that SME may be useful as an anti-photoaging resource for the skin. PMID:27573915

  4. A Broad-Spectrum Chemokine-Binding Protein of Bovine Papular Stomatitis Virus Inhibits Neutrophil and Monocyte Infiltration in Inflammatory and Wound Models of Mouse Skin

    PubMed Central

    Sharif, Saeed; Nakatani, Yoshio; Wise, Lyn; Corbett, Michael; Real, Nicola C.; Stuart, Gabriella S.; Lateef, Zabeen; Krause, Kurt; Mercer, Andrew A.; Fleming, Stephen B.

    2016-01-01

    Bovine papular stomatitis virus (BPSV) is a Parapoxvirus that induces acute pustular skin lesions in cattle and is transmissible to humans. Previous studies have shown that BPSV encodes a distinctive chemokine-binding protein (CBP). Chemokines are critically involved in the trafficking of immune cells to sites of inflammation and infected tissue, suggesting that the CBP plays a role in immune evasion by preventing immune cells reaching sites of infection. We hypothesised that the BPSV-CBP binds a wide range of inflammatory chemokines particularly those involved in BPSV skin infection, and inhibits the recruitment of immune cells from the blood into inflamed skin. Molecular analysis of the purified protein revealed that the BPSV-CBP is a homodimeric polypeptide with a MW of 82.4 kDa whilst a comprehensive screen of inflammatory chemokines by surface plasmon resonance showed high-affinity binding to a range of chemokines within the CXC, CC and XC subfamilies. Structural analysis of BPSV-CBP, based on the crystal structure of orf virus CBP, provided a probable explanation for these chemokine specificities at a molecular level. Functional analysis of the BPSV-CBP using transwell migration assays demonstrated that it potently inhibited chemotaxis of murine neutrophils and monocytes in response to CXCL1, CXCL2 as well as CCL2, CCL3 and CCL5 chemokines. In order to examine the effects of CBP in vivo, we used murine skin models to determine its impact on inflammatory cell recruitment such as that observed during BPSV infection. Intradermal injection of BPSV-CBP blocked the influx of neutrophils and monocytes in murine skin in which inflammation was induced with lipopolysaccharide. Furthermore, intradermal injection of BPSV-CBP into injured skin, which more closely mimics BPSV lesions, delayed the influx of neutrophils and reduced the recruitment of MHC-II+ immune cells to the wound bed. Our findings suggest that the CBP could be important in pathogenesis of BPSV infections

  5. Preparation of studies on antibody production against food allergens in mice and effect of flavonoids in simultaneous injection into mouse skin.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We had tried to evaluate antibody production against food allergens in mouse models. Some food allergens, which were beta-lactoglobulin, ovalbumin, and peanut allergen Ara h 1, were used as immunoges in this experiment. Under the same conditions these allergens were immunized as emulsion with freund...

  6. GENE EXPRESSION PROFILING OF MOUSE SKIN AND PAPILLOMAS FOLLOWING CHRONIC EXPOSURE TO MONOMETHYLARSONOUS ACID IN K6/ODC TRANSGENIC MICE

    EPA Science Inventory

    Methylarsonous acid [MMA(III)], a common metabolite of inorganic arsenic metabolism, increases tumor frequency in the skin of K6/ODC transgenic mice following a chronic exposure. To characterize gene expression profiles predictive of MMA(III) exposure and mode of action of carcin...

  7. Effects of 12-O-tetradecanoylphorbol-13-acetate on the incorporation of labelled precursors into RNA, DNA and protein in epidermis, dermis and subcutis from precancerous mouse skin with reference to enhanced tumorigenesis

    SciTech Connect

    Bhisey, R.A.; Ramchandani, A.G.; Sirsat, S.M.

    1984-02-01

    The effects of a single application of 1.8 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) on precursor incorporation into RNA, DNA and protein in the epidermis, dermis and subcutis from 3-methylcholanthrene (MCA) injected precancerous mouse skin were studied at various time points between 3 and 96 h. In the precancerous tissues, the rates of incorporation of (/sup 3/H)uridine into RNA did not alter appreciably from those in the control tissues; while the rates of (/sup 3/H)methylthymidine incorporation into DNA were elevated with peaks appearing between 6 and 12 h, at 24 h and at 72 h in epidermis, dermis and subcutis. The rate of incorporation of (/sup 14/C)leucine into protein was markedly elevated in all the three tissues which showed 3-4 sharp peaks. The maximum stimulation ranged between 14 and 20 times that of the control. A single application of TPA to the precancerous mouse skin induced early stimulation of precursor incorporation into all the three macromolecules in epidermis, dermis and subcutis. The increased stimulation was maintained for 36-72 h. The patterns of incorporation of (/sup 3/H)methylthymidine into DNA gave rise to 2-3 peaks of elevated uptake in each tissue up to 36-48 h. A lowered rate of DNA synthesis between 48 and 60 h was followed by a peak at 72 h. In each group, epidermal mitotic activity correlated well with spurts of precursor incorporation into cellular DNA. The observations indicate that TPA recruits more cells into the DNA synthetic phase and accelerates selective growth of preneoplastic cells during tumor progression.

  8. Inhibitory effects of chlorophyllin, hemin and tetrakis(4-benzoic acid)porphyrin on oxidative DNA damage and mouse skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate as a possible anti-tumor promoting mechanism.

    PubMed

    Park, Kwang Kyun; Park, Jae Hee; Jung, Youn Joo; Chung, Won Yoon

    2003-12-09

    Reactive oxygen species (ROS) from both endogenous and exogenous sources can cause oxidative DNA damage and dysregulated cell signaling, which are involved in the multistage process of carcinogenesis such as tumor initiation, promotion and progression. A number of structurally different anticarcinogenic agents inhibit inflammation and tumor promotion as they reduce ROS production and oxidative DNA damage. Evidence suggests that porphyrins can interfere with the actions of various carcinogens and mutagens by forming face-to-face complexes and their antimutagenic or antigenotoxic effects may also be attributed to their antioxidant activities. However, little is known regarding the anti-tumor promoting potential and mechanism of the porphyrin compounds. Based on our previous results on the inhibitory effects of chlorophyllin (CHL), hemin and tetrakis(4-benzoic acid)porphyrin (TBAP) against two-stage mouse skin carcinogenesis, we have investigated their anti-tumor promoting mechanisms. In the present work, CHL, hemin and TBAP reduced superoxide anion generation by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated HL-60 cells and the production of hydroxyl radicals by Fenton reaction. Porphyrins exert a dose-related inhibition of his(+) reversion in Salmonella typhimurium TA102 induced by tert-butylhydroperoxide (t-BOOH). DNA strand breaks by ROS derived from H(2)O(2)/Cu(II) and the formation of 8-hydroxydeoxyguanosine (8-OH-dG) in calf thymus DNA treated with H(2)O(2)/UV also were inhibited markedly by porphyrins in a concentration-dependent manner. Furthermore, CHL, hemin and TBAP decreased myeloperoxidase (MPO) activity and H(2)O(2) formation as well as epidermal ornithine decarboxylase (ODC) activity in mouse skin treated with TPA. These results demonstrate that the antioxidative properties of porphyrins are important for inhibiting TPA-induced tumor promotion.

  9. Skin Conditions

    MedlinePlus

    Your skin is your body's largest organ. It covers and protects your body. Your skin Holds body fluids in, preventing dehydration Keeps harmful ... it Anything that irritates, clogs, or inflames your skin can cause symptoms such as redness, swelling, burning, ...

  10. Aging Skin

    MedlinePlus

    ... email address Submit Home > Healthy Aging > Wellness Healthy Aging Aging skin More information on aging skin When it ... treated early. Return to top More information on Aging skin Read more from womenshealth.gov Varicose Veins ...

  11. Combinatorial chemopreventive effect of butyric acid, nicotinamide and calcium glucarate against the 7,12-dimethylbenz(a)anthracene induced mouse skin tumorigenesis attained by enhancing the induction of intrinsic apoptotic events.

    PubMed

    Tiwari, Prakash; Sahay, Satya; Pandey, Manuraj; Qadri, Syed S Y H; Gupta, Krishna P

    2015-01-25

    We explored the basis of the combinatorial chemopreventive effect of butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) on mouse skin exposed to 7,12-dimethylbenz(a)anthracene (DMBA). We studied the effects of topical application of DMBA in the presence or absence of BA, NA and CAG on the regulators of apoptosis. DMBA treatment suppressed Bax, Bax/Bcl-2 ratio, release of cyt c, Apaf1, caspase-9, -3 mediated apoptosis. Downregulation of p21 and upregulation of Bcl-2, mut p53 were also observed in only DMBA treated mice. Simultaneous application of BA, NA and CAG induced a mitochondria-mediated apoptosis, characterized by a rise in the Bax, Bax/Bcl-2 ratio, release of cyt c, upregulation of Apaf1 with down-stream activation of caspase-9, -3. Furthermore treatment with BA, NA and CAG demonstrated an upregulation of p21 and downregulation of Bcl-2, mut p53. But this effect was enhanced in the presence of all the three compounds together in combination. Chemoprevention by a combination of BA, NA and CAG by inducing the apoptosis, the natural cell death, suggest the importance of the potential combinational strategies capable of preventing skin tumor development.

  12. Cutaneous challenge with chemical warfare agents in the SKH-1 hairless mouse (II): effects of some currently used skin decontaminants (RSDL and Fuller's earth) against liquid sulphur mustard and VX exposure.

    PubMed

    Taysse, L; Dorandeu, F; Daulon, S; Foquin, A; Perrier, N; Lallement, G; Breton, P

    2011-06-01

    Using the hairless mouse screening model presented in the companion paper(1) the aim of this study was to assess two skin decontaminating systems: Fuller's earth (FE) and Reactive Skin Decontamination Lotion (RSDL) against two extremely toxic chemical warfare agents that represent a special percutaneous hazard, sulphur mustard (SM) and O-ethyl-S-(2[di-isopropylamino]ethyl)methyl-phosphonothioate (VX). Five minutes after being exposed on the back to either 2 µL of neat sulphur mustard or 50 µg.kg(-1) of diluted VX, mice were decontaminated. Both systems were able to reduce blisters 3 days after SM exposure. However, RSDL was found to be more efficient than FE in reducing the necrosis of the epidermis and erosion. In the case of VX exposure, RSDL, whatever the ratio of decontaminant to toxicant used (RSDL 10, 20, 50), was not able to sufficiently prevent the inhibition of plasma cholinesterases taken as a surrogate marker of exposure and toxicity. Only FE reduced significantly the ChE inhibition. Some of these observations are different from our previous results obtained in domestic swine and these changes are thus discussed in the perspective of using SKH-1 hairless mice for the initial in vivo screening of decontaminants.

  13. Chemopreventive activity of chlorophyllin against mouse skin carcinogenesis by benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide.

    PubMed

    Park, K K; Surh, Y J

    1996-04-19

    Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, was tested for its chemopreventive activity against tumorigenesis induced by benzo[a]pyrene (B[a]P) and its ultimate electrophilic and carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide(BPDE). Administration of CHL (15 mg/kg body wt) by gavage to female ICR mice 30 min prior to a topical application of B[a]P or BPDE resulted in significant reduction in both incidence and multiplicity of skin tumors initiated by these carcinogens. CHL was rapidly distributed in the skin and other tissues of mice after oral administration. Taken together, these results suggest that CHL is a potential chemopreventive agent.

  14. Skin abscess

    MedlinePlus

    Abscess - skin; Cutaneous abscess; Subcutaneous abscess; MRSA - abscess; Staph infection - abscess ... Skin abscesses are common and affect people of all ages. They occur when an infection causes pus ...

  15. Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/- or Rb1+/- backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling.

    PubMed

    Almeida, Madson Q; Muchow, Michael; Boikos, Sosipatros; Bauer, Andrew J; Griffin, Kurt J; Tsang, Kit Man; Cheadle, Chris; Watkins, Tonya; Wen, Feng; Starost, Matthew F; Bossis, Ioannis; Nesterova, Maria; Stratakis, Constantine A

    2010-04-15

    PRKAR1A inactivation leads to dysregulated cAMP signaling and Carney complex (CNC) in humans, a syndrome associated with skin, endocrine and other tumors. The CNC phenotype is not easily explained by the ubiquitous cAMP signaling defect; furthermore, Prkar1a(+/-) mice did not develop skin and other CNC tumors. To identify whether a Prkar1a defect is truly a generic but weak tumorigenic signal that depends on tissue-specific or other factors, we investigated Prkar1a(+/-) mice when bred within the Rb1(+/-) or Trp53(+/-) backgrounds, or treated with a two-step skin carcinogenesis protocol. Prkar1a(+/-) Trp53(+/-) mice developed more sarcomas than Trp53(+/-) mice (P < 0.05) and Prkar1a(+/-) Rb1(+/-) mice grew more (and larger) pituitary and thyroid tumors than Rb1(+/-) mice. All mice with double heterozygosity had significantly reduced life-spans compared with their single-heterozygous counterparts. Prkar1a(+/-) mice also developed more papillomas than wild-type animals. A whole-genome transcriptome profiling of tumors produced by all three models identified Wnt signaling as the main pathway activated by abnormal cAMP signaling, along with cell cycle abnormalities; all changes were confirmed by qRT-PCR array and immunohistochemistry. siRNA down-regulation of Ctnnb1, E2f1 or Cdk4 inhibited proliferation of human adrenal cells bearing a PRKAR1A-inactivating mutation and Prkar1a(+/-) mouse embryonic fibroblasts and arrested both cell lines at the G0/G1 phase of the cell cycle. In conclusion, Prkar1a haploinsufficiency is a relatively weak tumorigenic signal that can act synergistically with other tumor suppressor gene defects or chemicals to induce tumors, mostly through Wnt-signaling activation and cell cycle dysregulation, consistent with studies in human neoplasms carrying PRKAR1A defects.

  16. Preventive effects of butyric acid, nicotinamide, calcium glucarate alone or in combination during the 7, 12-dimethylbenz (a) anthracene induced mouse skin tumorigenesis via modulation of K-Ras-PI3K-AKTpathway and associated micro RNAs.

    PubMed

    Tiwari, Prakash; Sahay, Satya; Pandey, Manuraj; Qadri, Syed S Y H; Gupta, Krishna P

    2016-02-01

    Skin cancer is among the most common cancers worldwide and identifiable molecular changes for early and late stage of skin tumorigenesis can suggest the better targets for its control. In this study, we investigated the status of K-Ras-PI3K-AKTpathway followed by NF-κB, cyclin D1, MMP-9 and regulatory micro RNA during 7, 12-dimethylbenz[a]anthracene (DMBA) induced mouse skin tumorigenesis and its prevention by butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG), individually or in combination with respect to time. DMBA upregulated the K-Ras, PI3K, Akt, NF-κB, cyclin D1 and MMP-9, but downregulated the PTEN in a time dependent manner. DMBA also reduced the levels of micoRNA let-7a but induced the levels of miR-21 and miR-20a as a function of time. BA, NA and CAG were found to prevent DMBA induced changes, but they were most effective when used together in a combination. Reduced let-7a and miR-211 were correlated with the overexpression of K-Ras and MMP-9. Overexpression of miR-21 and miR-20a was correlated with the down regulation of PTEN and overexpression of Cyclin D1. Collectively, the enhanced chemopreventive potential of natural compound in combination via regulation of K-Ras-PI3K-AKTpathway along with regulatory micro RNAs provide a newer and effective mean for cancer management.

  17. Polyamines and nonmelanoma skin cancer

    SciTech Connect

    Gilmour, Susan K.

    2007-11-01

    Elevated levels of polyamines have long been associated with skin tumorigenesis. Tightly regulated metabolism of polyamines is critical for cell survival and normal skin homeostasis, and these controls are dysregulated in skin tumorigenesis. A key enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) is upregulated in skin tumors compared to normal skin. Use of transgenic mouse models has demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis. The formation of skin tumors in these transgenic mice is dependent upon polyamine biosynthesis, especially putrescine, since treatment with inhibitors of ODC activity blocks the formation of skin tumors and causes the rapid regression of existing tumors. Although the mechanism by which polyamines promote skin tumorigenesis are not well understood, elevated levels of polyamines have been shown to stimulate epidermal proliferation, alter keratinocyte differentiation status, increase neovascularization, and increase synthesis of extracellular matrix proteins in a manner similar to that seen in wound healing. It is becoming increasingly apparent that elevated polyamine levels activate not only epidermal cells but also underlying stromal cells in the skin to promote the development and progression of skin tumors. The inhibition of polyamine biosynthesis has potential to be an effective chemoprevention strategy for nonmelanoma skin cancer.

  18. The effect of multifunctional polymer-based gels on wound healing in full thickness bacteria-contaminated mouse skin wound models.

    PubMed

    Yates, Cecelia C; Whaley, Diana; Babu, Ranjith; Zhang, Jianying; Krishna, Priya; Beckman, Eric; Pasculle, A William; Wells, Alan

    2007-09-01

    We determined whether a two-part space-conforming polyethylene glycol/dopa polymer-based gel promoted healing of contaminated wounds in mice. This silver-catalysed gel was previously developed to be broadly microbiocidal in vitro while being biocompatible with human wound cell functioning. Full-thickness wounds were created on the backs of mice. The wounds were inoculated with 10(4) CFU of each of four common skin wound contaminants, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanii and Clostridium perfringens. The wounds were then treated with our multifunctional polymer-based gel, the commercially available NewSkin product, or left to heal untreated. The untreated wounds were overtly infected, and presented detectable bacterial loads over the entire 21-day healing period, while the gel and NewSkin groups presented significantly smaller rises in bacterial levels and were cleared of detectable colonies by the third week, with the gel group clearing the bacteria earlier. While all three groups healed their wounds, the polymer-based gel-treated group demonstrated significantly earlier re-epithelialization and dermal maturation (P<0.05). This was reflected in a quick regain of tensile strength. This accelerated dermal maturation and regain in strength was noted in mice treated with the polymer-based gel when compared to wound treated with the commercially available Aquacel-Ag dressing (P<0.05). What distinguishes the polymer-based gel from these other products is that it is incorporated within the healing wound. These preclinical studies show that the anti-microbial polymer gel not only supports but also accelerates healing of bacterially contaminated wounds.

  19. 5-HT1A/1B Receptors as Targets for Optimizing Pigmentary Responses in C57BL/6 Mouse Skin to Stress

    PubMed Central

    Wu, Hua-Li; Pang, Si-Lin; Liu, Qiong-Zhen; Wang, Qian; Cai, Min-Xuan; Shang, Jing

    2014-01-01

    Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A

  20. Skin Biomes.

    PubMed

    Fyhrquist, N; Salava, A; Auvinen, P; Lauerma, A

    2016-05-01

    The cutaneous microbiome has been investigated broadly in recent years and some traditional perspectives are beginning to change. A diverse microbiome exists on human skin and has a potential to influence pathogenic microbes and modulate the course of skin disorders, e.g. atopic dermatitis. In addition to the known dysfunctions in barrier function of the skin and immunologic disturbances, evidence is rising that frequent skin disorders, e.g. atopic dermatitis, might be connected to a dysbiosis of the microbial community and changes in the skin microbiome. As a future perspective, examining the skin microbiome could be seen as a potential new diagnostic and therapeutic target in inflammatory skin disorders.

  1. SBD.4 stimulates regenerative processes in vitro, and wound healing in genetically diabetic mice and in human skin/severe-combined immunodeficiency mouse chimera.

    PubMed

    Zhao, Hui; Mortezaei, Reza; Wang, Yanrong; Sheng, Xinsheng; Aria, Fariba; Bojanowski, Krzysztof

    2006-01-01

    In search of novel angiostimulators, we performed a high-throughput screening of medicinal plants beneficial for blood circulation. From the panel of positive hits, Angelica sinensis was selected for further investigation. Purified down to a low-molecular-weight fraction and characterized by high-performance liquid chromatography-mass spectrometry, the material, named SBD.4A, revealed a particularly strong wound healing activity in the diabetic mouse wound-healing model, and in the human/severe combined immunodeficiency mouse chimera wound-healing model. In both models, SBD.4A compared favorably with the Food and Drug Administration-approved wound-healing drug becaplermin, suggesting that this botanical product could be a valuable treatment for difficult-to-heal wounds. Further high-performance liquid chromatography fractionation of SBD.4A yielded a hydrophilic fraction, which strongly stimulated endothelial cell proliferation, tridimensional endothelial cell network formation, as well as the proliferation of human dermal fibroblasts and type I collagen secretion. Because angiogenesis and fibroblast proliferation are essential for wound healing, we propose that this liquid chromatography-mass spectrometry-defined hydrophilic fraction is at least partially responsible for the wound-healing activity of SBD.4A.

  2. Ultraviolet radiation-induced non-melanoma skin cancer in the Crl:SKH1:hr-BR hairless mouse: augmentation of tumor multiplicity by chlorophyllin and protection by indole-3-carbinol.

    PubMed

    Cope, R B; Loehr, C; Dashwood, R; Kerkvliet, N I

    2006-05-01

    Over 1 million new cases of ultraviolet radiation-induced non-melanoma skin cancers (NMSC) per year now occur in the USA and the incidence of these diseases continues to increase. New preventative strategies are required. The hypothesis tested was that dietary administration of the putative cancer chemopreventatives sodium-copper-chlorophyllin (Chlor) or indole-3-carbinol (I3C) would inhibit UV-induced skin carcinogenesis in the Crl:SKH1:hr-BR hairless mouse. Groups of 20 mice were pre-fed isocaloric/isonutritive 20% corn-oil AIN-76a based diets that contained either Chlor (1.52 g%), I3C (5.08 g%) or no chemopreventative (control) for 2 weeks followed by exposure of their dorsal skin to a 10 week incremental, sub-erythemal, carcinogenic simulated solar UV exposure regime. Feeding was continued for the duration of the experiment. Matched non-UV exposed dietary groups were also included in the experimental design. The diets had no significant (p > 0.05) effect on body weight, feed consumption, cutaneous methanol-extractable UV photoprotective substances or on cutaneous UV-reflective characteristics. By day 180, UV-irradiated mice fed the Chlor had a significantly (p < 0.05) higher tumor multiplicity (33.6 +/- 4.72; mean +/- SEM) than UV-irradiated control animals (22.8 +/- 4.25). UV-irradiated mice fed I3C had a significantly (p < 0.001) lower tumor multiplicity (13.0 +/- 2.42) than that of both the UV-irradiated control and UV-irradiated Chlor-fed mice. The Chlor or I3C diets did not significantly (p > 0.05) affect UV-induced systemic suppression of contact hypersensitivity responses. These results demonstrate augmentation of the UV-induced cutaneous carcinogenic process by dietary chlorophyllin and protection from this carcinogenic process by indole-3-carbinol via mechanisms that do not involve changes in skin optical properties, modulation of photoimmunosuppression or caloric/nutrient effects.

  3. Anti-wrinkle effects of Sargassum muticum ethyl acetate fraction on ultraviolet B-irradiated hairless mouse skin and mechanistic evaluation in the human HaCaT keratinocyte cell line.

    PubMed

    Song, Jae Hyoung; Piao, Mei Jing; Han, Xia; Kang, Kyoung Ah; Kang, Hee Kyoung; Yoon, Weon Jong; Ko, Mi Hee; Lee, Nam Ho; Lee, Mi Young; Chae, Sungwook; Hyun, Jin Won

    2016-10-01

    The present study investigated the photoprotective properties of the ethyl acetate fraction of Sargassum muticum (SME) against ultraviolet B (UVB)‑induced skin damage and photoaging in a mouse model. HR‑1 strain hairless male mice were divided into three groups: An untreated control group, a UVB‑irradiated vehicle group and a UVB‑irradiated SME group. The UVB‑irradiated mice in the SME group were orally administered with SME (100 mg/kg body weight in 0.1 ml water per day) and then exposed to radiation at a dose of 60‑120 mJ/cm2. Wrinkle formation and skin damage were evaluated by analysis of skin replicas, epidermal thickness and collagen fiber integrity in the dermal connective tissue. The mechanism underlying the action of SME was also investigated in the human HaCaT keratinocyte cell line following exposure of the cells to UVB at a dose of 30 mJ/cm2. The protein expression levels and activity of matrix metalloproteinase‑1 (MMP‑1), and the binding of activator protein‑1 (AP‑1) to the MMP‑1 promoter were assessed in the HaCaT cells using western blot analysis, an MMP‑1 fluorescent assay and a chromatin immune‑precipitation assay, respectively. The results showed that the mean length and depth of the wrinkles in the UVB‑exposed hairless mice were significantly improved by oral administration of SME, which also prevented the increase in epidermal thickness triggered by UVB irradiation. Furthermore, a marked increase in collagen bundle formation was observed in the UVB‑treated mice with SME administration. SME pretreatment also significantly inhibited the UVB‑induced upregulation in the expression and activity of MMP‑1 in the cultured HaCaT keratinocytes, and the UVB‑enhanced association of AP‑1 with the MMP‑1 promoter. These results suggested that SME may be useful as an anti-photoaging resource for the skin.

  4. Singlet oxygen luminescence as an in vivo photodynamic therapy dose metric: validation in normal mouse skin with topical amino-levulinic acid

    PubMed Central

    Niedre, M J; Yu, C S; Patterson, M S; Wilson, B C

    2005-01-01

    Although singlet oxygen (1O2) has long been proposed as the primary reactive oxygen species in photodynamic therapy (PDT), it has only recently been possible to detect it in biological systems by its luminescence at 1270 nm. Having previously demonstrated this in vitro and in vivo, we showed that cell survival was strongly correlated to the 1O2 luminescence in cell suspensions over a wide range of treatment parameters. Here, we extend this to test the hypothesis that the photobiological response in vivo is also correlated with 1O2 generation, independent of individual treatment parameters. The normal skin of SKH1-HR hairless mice was sensitised with 20% amino-levulinic acid-induced protoporophyrin IX and exposed to 5, 11, 22 or 50 J cm−2 of pulsed 523 nm light at 50 mW cm−2, or to 50 J cm−2 at 15 or 150 mW cm−2. 1O2 luminescence was measured during treatment and the photodynamic response of the skin was scored daily for 2 weeks after treatment. As observed by other authors, a strong irradiance dependence of the PDT effect was observed. However, in all cases the responses increased with the 1O2 luminescence, independent of the irradiance, demonstrating for the first time in vivo an unequivocal mechanistic link between 1O2 generation and photobiological response. PMID:15655542

  5. Lupeol induces p53 and cyclin-B-mediated G2/M arrest and targets apoptosis through activation of caspase in mouse skin

    SciTech Connect

    Nigam, Nidhi Prasad, Sahdeo; George, Jasmine; Shukla, Yogeshwer

    2009-04-03

    Lupeol, present in fruits and medicinal plants, is a biologically active compound that has been shown to have various pharmacological properties in experimental studies. In the present study, we demonstrated the modulatory effect of lupeol on 7,12-dimethylbenz[a]anthracene (DMBA)-induced alterations on cell proliferation in the skin of Swiss albino mice. Lupeol treatment showed significant (p < 0.05) preventive effects with marked inhibition at 48, 72, and 96 h against DMBA-mediated neoplastic events. Cell-cycle analysis showed that lupeol-induced G2/M-phase arrest (16-37%) until 72 h, and these inhibitory effects were mediated through inhibition of the cyclin-B-regulated signaling pathway involving p53, p21/WAF1, cdc25C, cdc2, and cyclin-B gene expression. Further lupeol-induced apoptosis was observed, as shown by an increased sub-G1 peak (28%) at 96 h, with upregulation of bax and caspase-3 genes and downregulation of anti-apoptotic bcl-2 and survivin genes. Thus, our results indicate that lupeol has novel anti-proliferative and apoptotic potential that may be helpful in designing strategies to fight skin cancer.

  6. Effect of treatment in fractionated schedules with the combination of x-irradiation and six cytotoxic drugs on the RIF-1 tumor and normal mouse skin

    SciTech Connect

    Lelieveld, P.; Scoles, M.A.; Brown, J.M.; Phil, D.; Kallman, R.F.

    1985-01-01

    RIF-1 tumors, implanted syngeneically in the gastrocnemius muscles of the right hind legs of C3H/Km mice, were treated either with X ray alone, drug alone, or drug and X ray combined. The drugs tested were bleomycin, BCNU, cis-diamminedichloro platinum, adriamycin, cyclophosphamide, and actinomycin-D. All drugs were administered either in the maximum tolerated dose or a dose that causes minimal tumor growth delay. Both drugs and X rays were administered either as a single dose or in five daily fractions. In addition to the single modality controls, seven different schedules of combined modalities were tested. Tumors were measured periodically after treatment in order that the day at which each tumor reached 4 times its initial cross-sectional area, i.e., its size at the time of treatment, could be determined. The effect of treatment on tumors was based upon excess growth delay (GD), i.e., T400% (treated)-T400% (untreated control). Treatment effects for the same combined modality schedules were also determined for normal skin, using the early skin reaction as an endpoint. Dose effect factors (DEF) were computed for all combined modality schedules and were based upon calculated radiation dose equivalents. We also calculated supra-additivity ratios, SR/sub I/ and SR/sub II/, therapeutic gain factors and adjusted therapeutic gain factors. The only drugs to produce significant supra-additivity with X rays were cis-Pt and cyclo.

  7. Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency.

    PubMed

    Flesch, Inge E A; Randall, Katrina L; Hollett, Natasha A; Di Law, Hsei; Miosge, Lisa A; Sontani, Yovina; Goodnow, Christopher C; Tscharke, David C

    2015-07-01

    DOCK8 deficiency in humans and mice leads to multiple defects in immune cell numbers and function. Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV). The underlying mechanism of the specific susceptibility to these chronic cutaneous viral infections is currently unknown, largely because the effect of DOCK8 deficiency has not been studied in suitable models. A better understanding of these mechanisms is required to underpin the development of more specific therapies. Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads. Furthermore, DOCK8-deficient mice showed a lack of CD4(+) T-cell infiltration into HSV-infected skin.

  8. Enhancement of tumor responsiveness to aminolevulinate-photodynamic therapy (ALA-PDT) using differentiation-promoting agents in mouse models of skin carcinoma

    NASA Astrophysics Data System (ADS)

    Anand, Sanjay; Honari, Golara; Paliwal, Akshat; Hasan, Tayyaba; Maytin, Edward V.

    2009-06-01

    Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is an emerging treatment for cancers. ALA, given as a prodrug, selectively accumulates and is metabolized in cancer cells to form protoporphyrin IX (PpIX). Targeted local irradiation with light induces cell death. Since the efficacy of ALA-PDT for large or deep tumors is currently limited, we are developing a new approach that combines differentiation-inducing agents with ALA-PDT to improve the clinical response. Here, we tested this new combination paradigm in the following two models of skin carcinoma in mice: 1) tumors generated by topical application of chemical carcinogens (DMBA-TPA); 2) human SCC cells (A431) implanted subcutaneously. To achieve a differentiated state of the tumors, pretreatment with a low concentration of methotrexate (MTX) or Vitamin D (Vit D) was administered for 72 h prior to exposure to ALA. Confocal images of histological sections were captured and digitally analyzed to determine relative PpIX levels. PpIX in the tumors was also monitored by real-time in vivo fluorescence dosimetry. In both models, a significant increase in levels of PpIX was observed following pretreatment with MTX or Vit D, as compared to no-pretreatment controls. This enhancing effect was observed at very low, non-cytotoxic concentrations, and was highly specific to cancer cells as compared to normal cells. These results suggest that use of differentiating agents such as MTX or Vit D, as a short-term combination therapy given prior to ALA-PDT, can increase the production of PpIX photosensitizer and enhance the therapeutic response of skin cancers.

  9. Modulation of miR-203 and its regulators as a function of time during the development of 7, 12 dimethylbenz [a] anthracene induced mouse skin tumors in presence or absence of the antitumor agents

    SciTech Connect

    Tiwari, Prakash; Gupta, Krishna P.

    2014-07-15

    We investigated the chemopreventive effects of naturally occurring compounds like butyric acid (BA), nicotinamide (NA) and calcium glucarate (CAG) individually or in combination in 7, 12-dimethylbenz [a] anthracene (DMBA) treated mouse skin at 4 and 16 weeks, the time before and after the tumor development. DMBA application did not show any skin tumors at 4 weeks but well defined tumors appeared at 16 weeks. BA, NA or CAG prevented the tumor development significantly but the protection was highly enhanced when all these compounds were given together. In order to see the molecular changes progressing with tumors, we showed the downregulation of tumor suppressor miR-203 at 16 weeks and upregulation of histone deacetylases (HDAC), DNA methyltransferase, promoter methylation of miR-203 at 4 or 16 weeks. Regulators of micro RNA biogenesis such as DICER1 and Ago2 were also deregulated by DMBA. Proto-oncogene c-myc and BMI1 were upregulated and tumor suppressor gene p16 was downregulated by DMBA as a function of time. Effects of BA, NA or CAG were more pronounced after 16 weeks as compared to 4 weeks in preventing the tumor development and altered gene expression. Concomitant administration of BA, NA and CAG tried to prevent these alterations more effectively than that of individual compound possibly by regulating miR-203 status through epigenetic or biogenetic modulations before and after the tumor development. Study provides a rationale for chemoprevention by combination of different compounds targeting miR-203. - Highlights: • DMBA modulates miR-203 and its regulator before and after the onset of tumors. • Suppression of miR-203 and p16 could be the result of gene promoter methylation. • BA, NA or CAG prevents the effects of DMBA. • Combination of BA, NA or CAG is more effective in preventing the DMBA modulations.

  10. Skin Infections

    MedlinePlus

    ... to the touch may have yellow drainage Of cellulitis: a red, inflamed area on the skin that is tender to the touch may occur in an area of a scratch or cut redness often spreads rapidly over the skin's surface ...

  11. Skin Pigment

    MedlinePlus

    ... Diseases Take Big Slice Out of America's Health, Economy (News) Health Tip: Use Caution When Applying Hair Dye Additional ... Skin Diseases Take Big Slice Out of America's Health, Economy THURSDAY, March 2, 2017 (HealthDay News) -- Skin diseases ...

  12. Sagging Skin

    MedlinePlus

    ... Stretch Marks Sun-damaged Skin Unwanted Hair Unwanted Tattoos Varicose Veins Vitiligo Wrinkles Treatments and Procedures Ambulatory ... Stretch Marks Sun-damaged Skin Unwanted Hair Unwanted Tattoos Varicose Veins Vitiligo Wrinkles Treatments and Procedures Ambulatory ...

  13. Effects of some natural carotenoids on TRPA1- and TRPV1-induced neurogenic inflammatory processes in vivo in the mouse skin.

    PubMed

    Horváth, Györgyi; Kemény, Ágnes; Barthó, Loránd; Molnár, Péter; Deli, József; Szente, Lajos; Bozó, Tamás; Pál, Szilárd; Sándor, Katalin; Szőke, Éva; Szolcsányi, János; Helyes, Zsuzsanna

    2015-05-01

    Mechanisms of the potent anti-inflammatory actions of carotenoids are unknown. Since carotenoids are incorporated into membranes, they might modulate transient receptor potential ankyrin 1 and vanilloid 1 (TRPA1 and TRPV1) activation predominantly on peptidergic sensory nerves. We therefore investigated the effects of three carotenoids (β-carotene, lutein and lycopene) on cutaneous neurogenic inflammation. Acute neurogenic edema and inflammatory cell recruitment were induced by smearing the TRPA1 agonist mustard oil (5%) or the TRPV1 activator capsaicin (2.5%) on the mouse ear. Ear thickness was then determined by micrometry, microcirculation by laser Doppler imaging and neutrophil accumulation by histopathology and spectrophotometric determination of myeloperoxidase activity. The effects of lutein on the stimulatory action of the TRPA1 agonist mustard oil were also tested on the guinea-pig small intestine, in isolated organ experiments. Mustard oil evoked 50-55% ear edema and granulocyte influx, as shown by histology and myeloperoxidase activity. Swelling was significantly reduced between 2 and 4 h after administration of lutein or β-carotene (100 mg/kg subcutane three times during 24 h). Lutein also decreased neutrophil accumulation induced by TRPA1 activation, but did not affect mustard oil-evoked intestinal contraction. Lycopene had no effect on any of these parameters. None of the three carotenoids altered capsaicin-evoked inflammation. It is proposed that the dihydroxycarotenoid lutein selectively inhibits TRPA1 activation and consequent neurogenic inflammation, possibly by modulating lipid rafts.

  14. Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina (Al2O3) nanoparticles in mouse skin epithelial cells.

    PubMed

    Dey, Swatee; Bakthavatchalu, Vasudevan; Tseng, Michael T; Wu, Peng; Florence, Rebecca L; Grulke, Eric A; Yokel, Robert A; Dhar, Sanjit Kumar; Yang, Hsin-Sheng; Chen, Yumin; St Clair, Daret K

    2008-10-01

    The physicochemical properties of nanomaterials differ from those of the bulk material of the same composition. However, little is known about the underlying effects of these particles in carcinogenesis. The purpose of this study was to determine the mechanisms involved in the carcinogenic properties of nanoparticles using aluminum oxide (Al(2)O(3)/alumina) nanoparticles as the prototype. Well-established mouse epithelial JB6 cells, sensitive to neoplastic transformation, were used as the experimental model. We demonstrate that alumina was internalized and maintained its physicochemical composition inside the cells. Alumina increased cell proliferation (53%), proliferating cell nuclear antigen (PCNA) levels, cell viability and growth in soft agar. The level of manganese superoxide dismutase, a key mitochondrial antioxidant enzyme, was elevated, suggesting a redox signaling event. In addition, the levels of reactive oxygen species and the activities of the redox sensitive transcription factor activator protein-1 (AP-1) and a longevity-related protein, sirtuin 1 (SIRT1), were increased. SIRT1 knockdown reduces DNA synthesis, cell viability, PCNA levels, AP-1 transcriptional activity and protein levels of its targets, JunD, c-Jun and BcL-xl, more than controls do. Immunoprecipitation studies revealed that SIRT1 interacts with the AP-1 components c-Jun and JunD but not with c-Fos. The results identify SIRT1 as an AP-1 modulator and suggest a novel mechanism by which alumina nanoparticles may function as a potential carcinogen.

  15. Melanogenesis inhibition by an oolong tea extract in b16 mouse melanoma cells and UV-induced skin pigmentation in brownish guinea pigs.

    PubMed

    Aoki, Yumi; Tanigawa, Tomoko; Abe, Hiroko; Fujiwara, Yoko

    2007-08-01

    To investigate the new physiological functions of oolong tea, the effects on melanogenesis were studied. An oolong tea extract inhibited melanogenesis without affecting cell growth in B16 mouse melanoma cells. However, the oolong tea extract hardly showed any inhibitory effect on mushroom tyrosinase in a cell-free system. The effects of an oolong tea extract on the intracellular tyrosinase level in B16 cells were therefore studied. All the levels of activity, protein and mRNA were decreased in the oolong tea extract-treated cells. We also investigated the inhibitory effects of oolong tea on the pigmentation induced by ultraviolet B (UVB) by using brownish guinea pigs in vivo. The number of 3,4-dihydroxyphenylalanine (DOPA)-positive melanocytes increased by UVB was repressed by an oral administration of oolong tea. These results imply that oolong tea might be effective in whitening and that its inhibitory effect on melanogenesis was involved in the decrease of intracellular tyrosinase at the mRNA level.

  16. Potentiation of UVB-induced apoptosis by novel phytosphingosine derivative, tetraacetyl phytosphingosine in HaCaT cell and mouse skin.

    PubMed

    Kim, H J; Kang, S-Y; Kim, S J; Kim, S H; Kim, T-Y

    2004-07-01

    Inappropriate apoptosis results in the epidermal hyperplasia as in psoriasis and UVB irradiation has been successfully used to treat this kind of skin disorders. Previously, we reported that the novel phytosphingosine derivative, tetraacetyl phytosphingosine (TAPS) induced apoptosis in HaCaT cells. This study examined the effect of UVB irradiation and/or TAPS on the induction of apoptosis in HaCaT. 10 mJ/cm2 of UVB irradiation or 10 microM of TAPS alone exhibited weak cytotoxicity but co-treatment of UVB and TAPS synergistically enhanced the cytotoxicity and apoptosis in HaCaT. The cells treated with UVB and TAPS showed much higher levels of cleaved caspase-3, -8, -9 and Bax than with UVB or TAPS alone, whereas Bcl-2 level was decreased by co-administration of UVB and TAPS. In hairless mice, co-treatment of UVB and TAPS synergistically increased apoptosis, as shown in the HaCaT co-treated with UVB and TAPS. Furthermore, UVB irradiation caused an increase of apoptotic cells in the epidermis and the TAPS-treated mice showed an increase of apoptotic cells in the dermis as well as in the epidermis. These results suggest that the TAPS co-treatment synergistically increases the level of UVB-induced apoptosis via caspase activation by regulating the level of pro-apoptotic Bax and anti-apoptotic Bcl-2.

  17. Up-regulation of clusterin during phthalocyanine 4 photodynamic therapy-mediated apoptosis of tumor cells and ablation of mouse skin tumors.

    PubMed

    Kalka, K; Ahmad, N; Criswell, T; Boothman, D; Mukhtar, H

    2000-11-01

    Photodynamic therapy (PDT) using the silicon phthalocyanine photo-sensitizer Pc 4 is an oxidative stress associated with the induction of apoptosis in many cancer cells in vitro and in vivo. The mechanisms of PDT-induced tumor cell killing leading to apoptosis are incompletely understood. Clusterin, a widely expressed glycoprotein, is induced in tissues regressing as a consequence of oxidative stress-mediated cell death. Treatment of apoptosis-sensitive human epidermoid carcinoma cells (A431) with PDT resulted in significant up-regulation of clusterin with a maximum at 12 h after treatment, whereas clusterin levels in Pc 4-PDT-treated, apoptosis-resistant, radiation-induced fibrosarcoma (RIF-1) cells remained unchanged. The i.v. administration of Pc 4 to mice bearing chemically or UVB radiation-induced skin papillomas, followed by light application, led to increased clusterin protein expression, peaking 24 h after the treatment, when tumor regression was apparently visible. These data, for the first time, demonstrate the involvement of clusterin in PDT-mediated cell death and during tumor regression. This may have relevance in improving the efficacy of PDT using pharmacological inducers of clusterin.

  18. Skin Aging

    MedlinePlus

    Your skin changes as you age. You might notice wrinkles, age spots and dryness. Your skin also becomes thinner and loses fat, making it ... heal, too. Sunlight is a major cause of skin aging. You can protect yourself by staying out ...

  19. BP-1107 [{2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide]: a novel synthetic thiazolidinedione that inhibits epidermal hyperplasia in psoriatic skin-severe-combined immunodeficient mouse transplants after topical application.

    PubMed

    Bhagavathula, Narasimharao; Nerusu, Kamalakar C; Reddy, Mahendranath; Ellis, Charles N; Chittiboyina, Amar; Avery, Mitchell; Pershadsingh, Harrihar A; Kurtz, Theodore W; Varani, James

    2005-12-01

    Recent studies have demonstrated that orally administered thiazolidinedione ligands of the peroxisome proliferator-activated receptor-gamma can ameliorate clinical features of psoriasis in humans. Thiazolidinediones also inhibit the proliferation of psoriatic keratinocytes in monolayer and organ culture, and at least one of these agents (troglitazone) inhibits epidermal hyperplasia of human psoriatic skin transplanted to severe-combined immunodeficient (SCID) mice. In the present study, we show that a novel, synthetic, thiazoladinedione derivative, BP-1107 ({2-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide), is capable of inhibiting psoriatic hyperplasia in the SCID mouse transplant model after topical application. Like other thiazolidinediones, BP-1107 inhibits proliferation of rapidly growing keratinocytes in monolayer culture, but compared with these agents, the effective dose of BP-1107 needed to suppress keratinocyte proliferation is much lower. Concentrations of BP-1107 that effectively inhibit keratinocyte function have no detrimental effect on dermal fibroblasts. These data suggest that effective topical antipsoriatic therapy may be provided with this agent.

  20. Application of a Fuzzy Neural Network Model in Predicting Polycyclic Aromatic Hydrocarbon- Mediated Perturbations of the Cyp1b1 Transcriptional Regulatory Network in Mouse Skin

    PubMed Central

    Larkin, Andrew; Siddens, Lisbeth K.; Krueger, Sharon K.; Tilton, Susan C.; Waters, Katrina M.; Williams, David E.; Baird, William M.

    2013-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave one out cross-validation. Predictions were within 1 log2 fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights. PMID:23274566

  1. Sensitive skin.

    PubMed

    Misery, L; Loser, K; Ständer, S

    2016-02-01

    Sensitive skin is a clinical condition defined by the self-reported facial presence of different sensory perceptions, including tightness, stinging, burning, tingling, pain and pruritus. Sensitive skin may occur in individuals with normal skin, with skin barrier disturbance, or as a part of the symptoms associated with facial dermatoses such as rosacea, atopic dermatitis and psoriasis. Although experimental studies are still pending, the symptoms of sensitive skin suggest the involvement of cutaneous nerve fibres and neuronal, as well as epidermal, thermochannels. Many individuals with sensitive skin report worsening symptoms due to environmental factors. It is thought that this might be attributed to the thermochannel TRPV1, as it typically responds to exogenous, endogenous, physical and chemical stimuli. Barrier disruptions and immune mechanisms may also be involved. This review summarizes current knowledge on the epidemiology, potential mechanisms, clinics and therapy of sensitive skin.

  2. Undergraduate Laboratory Module on Skin Diffusion

    ERIC Educational Resources Information Center

    Norman, James J.; Andrews, Samantha N.; Prausnitz, Mark R.

    2011-01-01

    To introduce students to an application of chemical engineering directly related to human health, we developed an experiment for the unit operations laboratory at Georgia Tech examining diffusion across cadaver skin in the context of transdermal drug delivery. In this laboratory module, students prepare mouse skin samples, set up diffusion cells…

  3. Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin

    SciTech Connect

    Larkin, Andrew; Siddens, Lisbeth K.; Krueger, Sharon K.; Tilton, Susan C.; Waters, Katrina M.; Williams, David E.; Baird, William M.

    2013-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave-one-out cross-validation. Predictions were within 1 log{sub 2} fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights. - Highlights: ► Tested a model to predict PAH mixture-mediated changes in Cyp1b1 expression ► Quantitative predictions in agreement with microarrays for Cyp1b1 induction ► Unexpected difference in expression between DBC and other treatments predicted ► Model predictions

  4. Skin aging and dry skin.

    PubMed

    Hashizume, Hideo

    2004-08-01

    Skin aging appears to be the result of both scheduled and continuous "wear and tear" processes that damage cellular DNA and proteins. Two types of aging, chronological skin aging and photoaging, have distinct clinical and histological features. Chronological skin aging is a universal and inevitable process characterized primarily by physiologic alterations in skin function. In this case, keratinocytes are unable to properly terminally differentiate to form a functional stratum corneum, and the rate of formation of neutral lipids that contribute to the barrier function slows, causing dry, pale skin with fine wrinkles. In contrast, photoaging results from the UVR of sunlight and the damage thus becomes apparent in sun-exposed skin. Characteristics of this aging type are dry and sallow skin displaying fine wrinkles as well as deep furrows, resulting from the disorganization of epidermal and dermal components associated with elastosis and heliodermatitis. Understanding of the functions of the skin and the basic principles of moisturizer use and application is important for the prevention of skin aging. Successful treatment of dry skin with appropriate skin care products gives the impression of eternal youth.

  5. Skin optics

    SciTech Connect

    van Gemert, M.J.; Jacques, S.L.; Sterenborg, H.J.; Star, W.M.

    1989-12-01

    Quantitative dosimetry in the treatment of skin disorders with (laser) light requires information on propagation of light in the skin related to the optical properties of the individual skin layers. This involves the solution of the integro-differential equation of radiative transfer in a model representing skin geometry, as well as experimental methods to determine the optical properties of each skin layer. These activities are unified under the name skin optics. This paper first reviews the current status of tissue optics, distinguishing between the cases of: dominant absorption, dominant scattering, and scattering about equal to absorption. Then, previously published data as well as some current unpublished data on (human) stratum corneum, epidermis and dermis, have been collected and/or (re)analyzed in terms of absorption coefficient, scattering coefficient, and anisotropy factor of scattering. The results are that the individual skin layers show strongly forward scattering (anisotropy factors between 0.7 and 0.9). The absorption and scattering data show that for all wavelengths considered scattering is much more important than absorption. Under such circumstances, solutions to the transport equation for a multilayer skin model and finite beam laser irradiation are currently not yet available. Hence, any quantitative dosimetry for skin treated with (laser) light is currently lacking.

  6. Inositoylated platelet-activating factor (Ino-C2-PAF) modulates dynamic lymphocyte-endothelial cell interactions and alleviates psoriasis-like skin inflammation in two complementary mouse models.

    PubMed

    Forkel, Susann; Schön, Margarete; Hildmann, Annette; Claßen, Anna; John, Swen-Malte; Danker, Kerstin; Schön, Michael P

    2014-10-01

    Psoriasis, a tumor necrosis factor alpha (TNFα)-governed inflammatory disorder with prominent dysregulation of cutaneous vascular functions, has evolved into a model disorder for studying anti-inflammatory therapies. We present experimental in vitro and in vivo data on 1-O-octadecyl-2-O-(2-(myo-inositolyl)-ethyl)-sn-glycero-3-(R/S)-phosphatidyl-choline (Ino-C2-PAF), the lead compound of a class of synthetic glycosylated phospholipids, in anti-inflammatory therapy. Ino-C2-PAF strongly induced apoptosis only in TNFα-stimulated, but not in untreated human vascular endothelial cells. Moreover, TNFα-induced endothelial adhesion molecules that mediated the rolling and firm adhesion of leukocytes (vascular cell adhesion protein-1 (VCAM-1), E-selectin, and ICAM-1) were selectively downregulated by Ino-C2-PAF. Similarly, expression of L-selectin, VCAM-1 receptor α4β1 integrin , and lymphocyte function-associated antigen-1 on human peripheral blood mononuclear cells was reduced without induction of apoptosis. Functionally, these changes were accompanied by significant impairment of rolling and adhesion of human peripheral blood lymphocytes on TNFα-activated endothelial cells in a dynamic flow chamber system. When the therapeutic potential of Ino-C2-PAF was assessed in two complementary mouse models of psoriasis, K5.hTGFβ1 transgenic and JunB/c-Jun-deficient mice, Ino-C2-PAF led to significant alleviation of the clinical symptoms and normalized the pathological cutaneous changes including vascularization. There were no overt adverse effects. These findings suggested that Ino-C2-PAF is a potential candidate in the therapy of inflammatory skin diseases that include abnormal vascular functions.

  7. Skin findings in newborns

    MedlinePlus

    Newborn skin characteristics; Infant skin characteristics; Neonatal care - skin ... the first few weeks of the baby's life. Newborn skin will vary, depending on the length of the pregnancy. Premature infants have thin, transparent skin. The skin of a ...

  8. Skin Infections

    MedlinePlus

    ... it can get infected by them. Some common types of skin infections are Bacterial: Cellulitis and impetigo. Staphylococcal infections can also affect the skin. Viral: Shingles, warts, and herpes simplex Fungal: Athlete's foot and yeast infections Parasitic: Body lice, head lice, and scabies ...

  9. Skin Cancer

    MedlinePlus

    ... exposure to ultraviolet light, which is found in sunlight and in lights used in tanning salons.What ... the safe-sun guidelines.1. Avoid the sun.Sunlight damages your skin. The sun is strongest during ...

  10. Skin graft

    MedlinePlus

    ... that need skin grafts to heal Venous ulcers, pressure ulcers , or diabetic ulcers that do not heal Very ... chap 17. Read More Burns Patient Instructions Preventing pressure ulcers Surgical wound care - open Review Date 3/13/ ...

  11. Your Skin

    MedlinePlus

    ... wear sunscreen and protective clothing, such as a hat, to prevent painful sunburns. Protecting your skin now ... happens in a split second, without you ever thinking about it. previous continue Dermis = Lots of Blood ...

  12. Skin Cancer

    MedlinePlus

    ... States. The two most common types are basal cell cancer and squamous cell cancer. They usually form on the head, face, ... If not treated, some types of skin cancer cells can spread to other tissues and organs. Treatments ...

  13. Comparative grepafloxacin phototoxicity in mouse skin.

    PubMed

    Owen, K

    1998-08-01

    This study was performed in order to compare the phototoxic potential of grepafloxacin (a new fluoroquinolone for the treatment of respiratory tract infections) with that of a number of marketed fluoroquinolones. Groups of Balb/c mice received either control material or grepafloxacin, lomefloxacin, sparfloxacin, ofloxacin, ciprofloxacin or enoxacin at an oral dose of 200 mg/kg before being exposed to 20 J/cm2 longwave ultraviolet irradiation for 110-115 min. Lomefloxacin and sparfloxacin caused erythema and oedema which were often severe and lasted the full 7 days of the study. Enoxacin caused a long-lasting erythema, while the erythema seen following the administration of grepafloxacin, ciprofloxacin and ofloxacin was relatively mild and short-lived. The results of this study demonstrate the good safety profile of grepafloxacin in terms of phototoxicity.

  14. Senescent Skin

    PubMed Central

    Kushniruk, William

    1974-01-01

    The cutaneous surface is continually influenced by aging and environmental factors. A longer life span is accompanied by an increase in the frequency of problems associated with aging skin. Although most of these changes and lesions are not life threatening, the premalignant lesions must be recognized and treated. The common aging and actinic skin changes are discussed and appropriate management is described. ImagesFig. 1Fig. 2Fig. 3Fig. 4 PMID:20469067

  15. A skin-inspired organic digital mechanoreceptor

    NASA Astrophysics Data System (ADS)

    Tee, Benjamin C.-K.; Chortos, Alex; Berndt, Andre; Nguyen, Amanda Kim; Tom, Ariane; McGuire, Allister; Lin, Ziliang Carter; Tien, Kevin; Bae, Won-Gyu; Wang, Huiliang; Mei, Ping; Chou, Ho-Hsiu; Cui, Bianxiao; Deisseroth, Karl; Ng, Tse Nga; Bao, Zhenan

    2015-10-01

    Human skin relies on cutaneous receptors that output digital signals for tactile sensing in which the intensity of stimulation is converted to a series of voltage pulses. We present a power-efficient skin-inspired mechanoreceptor with a flexible organic transistor circuit that transduces pressure into digital frequency signals directly. The output frequency ranges between 0 and 200 hertz, with a sublinear response to increasing force stimuli that mimics slow-adapting skin mechanoreceptors. The output of the sensors was further used to stimulate optogenetically engineered mouse somatosensory neurons of mouse cortex in vitro, achieving stimulated pulses in accordance with pressure levels. This work represents a step toward the design and use of large-area organic electronic skins with neural-integrated touch feedback for replacement limbs.

  16. A skin-inspired organic digital mechanoreceptor.

    PubMed

    Tee, Benjamin C-K; Chortos, Alex; Berndt, Andre; Nguyen, Amanda Kim; Tom, Ariane; McGuire, Allister; Lin, Ziliang Carter; Tien, Kevin; Bae, Won-Gyu; Wang, Huiliang; Mei, Ping; Chou, Ho-Hsiu; Cui, Bianxiao; Deisseroth, Karl; Ng, Tse Nga; Bao, Zhenan

    2015-10-16

    Human skin relies on cutaneous receptors that output digital signals for tactile sensing in which the intensity of stimulation is converted to a series of voltage pulses. We present a power-efficient skin-inspired mechanoreceptor with a flexible organic transistor circuit that transduces pressure into digital frequency signals directly. The output frequency ranges between 0 and 200 hertz, with a sublinear response to increasing force stimuli that mimics slow-adapting skin mechanoreceptors. The output of the sensors was further used to stimulate optogenetically engineered mouse somatosensory neurons of mouse cortex in vitro, achieving stimulated pulses in accordance with pressure levels. This work represents a step toward the design and use of large-area organic electronic skins with neural-integrated touch feedback for replacement limbs.

  17. Skin lumps

    MedlinePlus

    ... DM. Dermal and subcutaneous tumors. In: James WD, Berger TG, Elston DM, eds. Andrews' Diseases of the Skin: Clinical ... Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the ...

  18. Evaluation of animal models for predicting skin penetration in man.

    PubMed

    Reifenrath, W G; Chellquist, E M; Shipwash, E A; Jederberg, W W

    1984-04-01

    The human skin grafted athymic nude mouse, pig skin grafted athymic nude mouse, hairless dog, and weanling Yorkshire pig were evaluated as models for predicting skin penetration in man. Nine radiolabeled compounds previously tested on man were applied topically (4 micrograms/cm2) to each animal. These compounds included caffeine, benzoic acid, N,N-diethyl-m-toluamide, three steroids, and three insecticides. To correct for incomplete excretion of the label following topical absorption, percentage penetration was calculated by dividing the percentage of the topically applied radioactive dose recovered in the excreta by the corresponding percentage after parenteral administration and multiplication by 100. In the case of the grafted athymic nude mouse, calculated values of percentage penetration were confirmed because significant correlations (r = 0.78 for the human skin grafted athymic nude mouse and r = 0.97 for the pig skin grafted athymic nude mouse) were found between the calculated values and percentage penetration determined by summing radioactivity recovered in the urine, feces, tissues, and carcass. The results revealed a significant correlation between human skin grafted athymic nude mouse values and human values (r = 0.74, p = 0.05), and between weanling Yorkshire pig values and human values (r = 0.83, p = 0.05). In contrast, no significant correlation existed between human values and those of the hairless dog and pig skin grafted athymic nude mouse. The disposition of radioactivity following topical application of the radiolabeled nerve agent analog ( diisopropylfluorophosphonate ) and simulant (diethyl malonate) was determined in the weanling pig and the human skin grafted athymic nude mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Skin Cancer Foundation

    MedlinePlus

    ... Host a Fundraising Event | About Us | Store The Skin Cancer Foundation The Skin Cancer Foundation is the ... Handbook A "Sunscreen Gene"? Skin Cancer Facts & Statistics Skin Cancer Treatment Glossary Information on medications and procedures ...

  20. Skin Pigmentation Disorders

    MedlinePlus

    Pigmentation means coloring. Skin pigmentation disorders affect the color of your skin. Your skin gets its color from a pigment called melanin. Special cells in the skin make melanin. When these cells become damaged or ...

  1. Autoinflammatory Skin Disorders: The Inflammasomme in Focus.

    PubMed

    Gurung, Prajwal; Kanneganti, Thirumala-Devi

    2016-07-01

    Autoinflammatory skin disorders are a group of heterogeneous diseases that include diseases such as cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF). Therapeutic strategies targeting IL-1 cytokines have proved helpful in ameliorating some of these diseases. While inflammasomes are the major regulators of IL-1 cytokines, inflammasome-independent complexes can also process IL-1 cytokines. Herein, we focus on recent advances in our understanding of how IL-1 cytokines, stemming from inflammasome-dependent and -independent pathways are involved in the regulation of skin conditions. Importantly, we discuss several mouse models of skin inflammation generated to help elucidate the basic cellular and molecular effects and modulation of IL-1 in the skin. Such models offer perspectives on how these signaling pathways could be targeted to improve therapeutic approaches in the treatment of these rare and debilitating inflammatory skin disorders.

  2. Cutaneous skin tag

    MedlinePlus

    Skin tag; Acrochordon; Fibroepithelial polyp ... have diabetes. They are thought to occur from skin rubbing against skin. ... The tag sticks out of the skin and may have a short, narrow stalk connecting it to the surface of the skin. Some skin tags are as long as ...

  3. Skin Diseases in Laboratory Mice: Approaches to Drug Target Identification and Efficacy Screening

    PubMed Central

    Sundberg, John P.; Silva, Kathleen A.; King, Lloyd E.; Pratt, C. Herbert

    2017-01-01

    A large variety of mouse models for human skin, hair, and nail diseases are readily available from investigators and vendors worldwide. Mouse skin is a simple organ to observe lesions and their response to therapy, but identifying and monitoring the progress of treatments of mouse skin diseases can still be challenging. This chapter provides an overview on how to use the laboratory mouse as a preclinical tool to evaluate efficacy of new compounds or test potential new uses for compounds approved for use for treating an unrelated disease. Basic approaches to handling mice, applying compounds, and quantifying effects of the treatment are presented. PMID:27150092

  4. Skin Keratins

    PubMed Central

    Wang, Fengrong; Zieman, Abigail; Coulombe, Pierre A.

    2016-01-01

    Keratins comprise the type I and type II intermediate filament-forming proteins and occur primarily in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Keratins serve multiple homeostatic and stress-enhanced mechanical and nonmechanical functions in epithelia, including the maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications as well as keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility and/or altered tissue homeostasis. Moreover, keratin mutation or misregulation represents risk factors or genetic modifiers for several acute and chronic diseases. This chapter focuses on keratins that are expressed in skin epithelia, and details a number of basic protocols and assays that have proven useful for analyses being carried out in skin. PMID:26795476

  5. Induction of anti-EBNA-1 protein by 12-O-tetradecanoylphorbol-13-acetate treatment of human lymphoblastoid cells

    SciTech Connect

    Wen, Longthung; Tanaka, Akiko; Nonoyama, Meihan )

    1989-08-01

    Binding of the Epstein-Barr virus (EBV) nuclear antigen (EBNA-1) to BamHI-C DNA was studied by affinity column chromatography followed by immunoblotting with human serum specific for EBNA-1. Two species of EBNA-1 (68 and 70 kilodaltons) were identified in nuclear extracts of the EBV-positive Burkitt's lymphoma cell line Raji and not in nuclear extracts of the EBV-negative Burkitt's lymphoma cell line BJAB. Both EBNA-1s bound specifically to the region required for EBV plasmid DNA maintenance (oriP) located in the BamHI-C fragment. Upon treatment with 12-O-tetradecanoylphorbol-13-acetate, which activates latent EBV genome in Raji cells, the 68-kilodalton EBNA-1 was uncoupled from binding to EBV oriP. Nuclear extracts from 12-O-tetradecanoylphorbol-13-acetate-treated BJAB cells also uncoupled the binding of both EBNA-1s to oriP. DNA-cellulose column chromatography identified two protein species which competed for and uncoupled the binding of EBNA-1 to oriP. The two cellular competitors the authors called anti-EBNA-1 proteins had molecular masses of 60 and 40 kilodaltons, respectively. They were not found in nuclear extracts of BJAB cells not activated by 12-O-tetradecanoylphorbol-13-acetate.

  6. Skin (Pressure) Sores

    MedlinePlus

    ... Treatments and Side Effects Managing Cancer-related Side Effects Skin Problems Pressure Sores A skin or pressure sore ... Content Usage Policy . Skin Problems Dry Skin Itching Skin Color Changes Pressure Sores Scars ... and Paying for Treatment Treatments and Side Effects Survivorship: During and After Treatment Caregivers and Family ...

  7. Cellularized Bilayer Pullulan-Gelatin Hydrogel for Skin Regeneration.

    PubMed

    Nicholas, Mathew N; Jeschke, Marc G; Amini-Nik, Saeid

    2016-05-01

    Skin substitutes significantly reduce the morbidity and mortality of patients with burn injuries and chronic wounds. However, current skin substitutes have disadvantages related to high costs and inadequate skin regeneration due to highly inflammatory wounds. Thus, new skin substitutes are needed. By combining two polymers, pullulan, an inexpensive polysaccharide with antioxidant properties, and gelatin, a derivative of collagen with high water absorbency, we created a novel inexpensive hydrogel-named PG-1 for "pullulan-gelatin first generation hydrogel"-suitable for skin substitutes. After incorporating human fibroblasts and keratinocytes onto PG-1 using centrifugation over 5 days, we created a cellularized bilayer skin substitute. Cellularized PG-1 was compared to acellular PG-1 and no hydrogel (control) in vivo in a mouse excisional skin biopsy model using newly developed dome inserts to house the skin substitutes and prevent mouse skin contraction during wound healing. PG-1 had an average pore size of 61.69 μm with an ideal elastic modulus, swelling behavior, and biodegradability for use as a hydrogel for skin substitutes. Excellent skin cell viability, proliferation, differentiation, and morphology were visualized through live/dead assays, 5-bromo-2'-deoxyuridine proliferation assays, and confocal microscopy. Trichrome and immunohistochemical staining of excisional wounds treated with the cellularized skin substitute revealed thicker newly formed skin with a higher proportion of actively proliferating cells and incorporation of human cells compared to acellular PG-1 or control. Excisional wounds treated with acellular or cellularized hydrogels showed significantly less macrophage infiltration and increased angiogenesis 14 days post skin biopsy compared to control. These results show that PG-1 has ideal mechanical characteristics and allows ideal cellular characteristics. In vivo evidence suggests that cellularized PG-1 promotes skin regeneration and may

  8. Stages of Skin Cancer

    MedlinePlus

    ... Skin Cancer Skin color and being exposed to sunlight can increase the risk of nonmelanoma skin cancer ... carcinoma include the following: Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) ...

  9. Skin Cancer Treatment

    MedlinePlus

    ... Skin Cancer Skin color and being exposed to sunlight can increase the risk of nonmelanoma skin cancer ... carcinoma include the following: Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) ...

  10. Basal cell skin cancer

    MedlinePlus

    ... occur on skin that is regularly exposed to sunlight or other ultraviolet radiation. This type of skin ... skin cancer is to reduce your exposure to sunlight . Always use sunscreen: Apply sunscreen with sun protection ...

  11. Skin Condition Finder

    MedlinePlus

    ... SKIN CONDITIONS HEALTH TOPICS FOR PROFESSIONALS Rash and Skin Condition Finder 1 Select Age Group Infant Child ... Toe Toe Webspace Toe Nail CLOSE About the Skin Condition Finder Have a health question or concern? ...

  12. Skin Complications of IBD

    MedlinePlus

    ... Home > Resources > Skin Complications of IBD Go Back Skin Complications of IBD Email Print + Share After arthritis, ... about 5% of people with inflammatory bowel disease. SKIN DISORDERS COMMONLY SEEN IN IBD ERHTHEMA NODOSUM The ...

  13. Scalded skin syndrome

    MedlinePlus

    Ritter disease; Staphylococcal scalded skin syndrome (SSS) ... Scalded skin syndrome (SSS) is caused by infection with certain strains of Staphylococcus bacteria. The bacteria produce a toxin that causes the skin ...

  14. Skin Allergy Quiz

    MedlinePlus

    ... time. Some common medications that can cause skin allergy include penicillin, sulfa drugs, barbiturates and anticonvulsants just to mention a few. Some of the symptoms from drug allergies might be hives, skin rash, itchy skin or ...

  15. Learning about Skin Cancer

    MedlinePlus

    ... Why Deadly Skin Cancers Spread 2000 News Release Learning About Skin Cancer What are the most common ... skin surface. When a melanoma becomes thick and deep, the disease often spreads to other parts of ...

  16. The influence of cosmetics on the properties of skin autofluorescence

    NASA Astrophysics Data System (ADS)

    Tamošiūnas, M.; Bertulytė, I.; Rečiūnaitė, I.; Jakštys, B.; Šatkauskienė, I.; Čepurnienė, K.

    2014-10-01

    The aim of this study was to estimate the changes of autofluorescence and sensitized fluorescence under the effect of cosmetics. We used a method of fluorescence spectroscopy in vivo and examined the mouse skin covering the tumour. Analysis of fluorescence spectral changes was made after differentiation of the cosmetics according to its effects: i) inducing temporary changes of skin autofluorescence after absorbtion into skin (lipsticks, face powders, body lotions, mascaras); ii) permanently changing the fluorescence of the skin (collagen containing products). Cosmetics have been shown to be optically active and capable to alter the fluorescence of exogenously accumulated photosensitizers and endogenous tissue fluorophores.

  17. Stem cells of the skin epithelium

    PubMed Central

    Alonso, Laura; Fuchs, Elaine

    2003-01-01

    Tissue stem cells form the cellular base for organ homeostasis and repair. Stem cells have the unusual ability to renew themselves over the lifetime of the organ while producing daughter cells that differentiate into one or multiple lineages. Difficult to identify and characterize in any tissue, these cells are nonetheless hotly pursued because they hold the potential promise of therapeutic reprogramming to grow human tissue in vitro, for the treatment of human disease. The mammalian skin epithelium exhibits remarkable turnover, punctuated by periods of even more rapid production after injury due to burn or wounding. The stem cells responsible for supplying this tissue with cellular substrate are not yet easily distinguishable from neighboring cells. However, in recent years a significant body of work has begun to characterize the skin epithelial stem cells, both in tissue culture and in mouse and human skin. Some epithelial cells cultured from skin exhibit prodigious proliferative potential; in fact, for >20 years now, cultured human skin has been used as a source of new skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of stem cells. Cell fate choices, including both self-renewal and differentiation, are crucial biological features of stem cells that are still poorly understood. Skin epithelial stem cells represent a ripe target for research into the fundamental mechanisms underlying these important processes. PMID:12913119

  18. Skin to skin care:heat balance.

    PubMed Central

    Karlsson, H

    1996-01-01

    Skin to skin care has been practised in primitive and high technology cultures for body temperature preservation in neonates. Regional skin temperature and heat flow was measured in moderately hypothermic term neonates to quantitate the heat transfer occurring during one hour of skin to skin care. Nine healthy newborns with a mean rectal temperature of 36.3 degrees C were placed skin to skin on their mothers' chests. The mean (SD) rectal temperature increased by 0.7 (0.4) degrees C to 37.0 degrees C. The heat loss was high (70 Wm-2) from the unprotected skin of the head to the surrounding air. Minute heat losses occurred from covered areas; and heat was initially gained from areas in contact with the mother's skin. The total dry heat loss during skin to skin care corresponded to heat loss during incubator care at 32-32.5 degrees C. The reduced heat loss, and to a minor extent, the initial heat flux from the mothers allowed heat to be conserved, leading to rewarming. PMID:8949698

  19. Chemically induced skin carcinogenesis: Updates in experimental models (Review)

    PubMed Central

    NEAGU, MONICA; CARUNTU, CONSTANTIN; CONSTANTIN, CAROLINA; BODA, DANIEL; ZURAC, SABINA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

    2016-01-01

    Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

  20. Skin Care and Aging

    MedlinePlus

    ... version of this page please turn Javascript on. Skin Care and Aging How Aging Affects Skin Your skin changes with age. It becomes thinner, ... to make it feel and look better. Dry Skin and Itching Click for more information Many older ...

  1. Acne in ethnic skin.

    PubMed

    Halder, Rebat M; Brooks, Howard L; Callender, Valerie D

    2003-10-01

    Acne is the most common disorder observed in ethnic skin. Clinical presentation is different than in white skin. Postinflammatory hyperpigmentation is a common sequelae of acne in darker skin. The management of acne in ethnic skin is based largely on the prevention and treatment of hyperpigmentation.

  2. Human papillomaviruses and skin cancer.

    PubMed

    Smola, Sigrun

    2014-01-01

    Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 120 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood. The clinical relevance of genus beta-PV infection has clearly been demonstrated in patients suffering from epidermodysplasia verruciformis (EV), a rare inherited disease associated with ahigh rate of skin cancer. In the normal population genus beta-PV are suspected to have an etiologic role in skin carcinogenesis as well but this is still controversially discussed. Their oncogenic potency has been investigated in mouse models and in vitro. In 2009, the International Agency for Research on Cancer (IARC) classified the genus beta HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. This chapter will give an overview on the knowns and unknowns of infections with genus beta-PV and discuss their potential impact on skin carcinogenesis in the general population.

  3. Estrogens and aging skin

    PubMed Central

    Thornton, M. Julie

    2013-01-01

    Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. Estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. Estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. Its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer.   Skin aging can be significantly delayed by the administration of estrogen. This paper reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SERMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. Understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies. PMID:24194966

  4. Effect of 8-methoxypsoralen plus long-wave ultraviolet (PUVA) radiation on mast cells: PUVA suppresses degranulation of mouse skin mast cells induced by compound 48/80 or concanavalin A

    SciTech Connect

    Danno, K.; Toda, K.; Horio, T.

    1985-08-01

    Ears of mice were treated with a 0.5% 8-MOP solution topically plus UVA radiation (1.5-2.5 J/cm2). After PUVA radiation, skin responses to intradermal injection with mast cell liberators, including compound 48/80 (2.5 mg/ml, 10 microliter) and concanavalin A (Con-A) (2.0 mg/ml), or with a mixture of 5-hydroxytryptamine (5-HT) and histamine as vasodilator (1.0 mg/ml and 50 mM, respectively) were examined with time (2 h-14 days). At each time point, an ear swelling response (ESR) was measured with a dial thickness gauge. The rate of mast cell degranulation and mast cell numbers were assessed by light microscopy using toluidine blue-stained semithin (1 micron) sections. ESR induced by compound 48/80 or Con-A was significantly suppressed dose-dependently (greater than 42% inhibition) by PUVA between 2 h-3 days postirradiation as compared with that in nonirradiated control mice, and the value returned to normal levels by 7-14 days. Compound 48/80- or Con-A-induced mast cell degranulation (%) was remarkably decreased between 2 h-3 days (greater than 48% inhibition) in accordance with the suppression in ESR and it was restored to the rates in nonirradiated controls by 7-14 days. Neither ESR nor percent degranulation was affected by UVA radiation only (less than 3.5 J/cm2) or application of 8-MOP only. 5-HT plus histamine-mediated ESR was not altered at all by PUVA throughout the experimental period. Since PUVA radiation itself at given doses did not produce measurable ESR, mast cell degranulation, or a reduction in mast cell numbers, and since PUVA did not affect a normal vascular response to vasodilator, it seemed that decreased skin reactivity to mast cell degranulators by PUVA might be due to a PUVA-induced noncytolytic alteration in mast cell release mechanisms.

  5. Sensitivity of mouse Skh:HR-2 to ultraviolet radiation: melanocyte inactivation

    SciTech Connect

    Warren, R.; Gardner, P.A.; Reed, J.C.

    1987-03-01

    The hairless mouse, Skh:HR-2, was exposed to doses of ultraviolet (UV) radiation known to induce skin pigmentation. Three parameters associated with perturbations in skin pigmentation were monitored following UV exposure. These include spectroscopy (skin darkness), histology (melanocyte density), and biochemistry (melanin). Within 90 min of UV exposure, the skin became lighter. This was associated with a reduction of quantifiable melanin and the inactivation of epidermal melanocytes.

  6. [Psoriasis SCID-mouse model].

    PubMed

    Pfeffer, J; Kaufmann, R; Boehncke, W-H

    2006-07-01

    Psoriasis is characterized by a complex phenotype and pathogenesis along with polygenic determination. Several psoriasis animal models have only been able to incompletely reproduce the disease. A xenogeneic transplantation approach, grafting skin from psoriatic patients onto mice with a severe combined immunodeficiency (SCID), was the first to meet the criteria for a psoriasis model. During the last 10 years, this psoriasis SCID-mouse model not only allowed telling experiments focusing on pathogenetic aspects, but also proved being a powerful tool for drug discovery with a good predictive value.

  7. Radiation therapy - skin care

    MedlinePlus

    ... numbness Skin sores Most of these symptoms will go away after your treatments have stopped. However, your skin may remain darker, drier, and more sensitive to the sun. When your hair grows back, it may be different than before.

  8. Squamous cell skin cancer

    MedlinePlus

    ... occur on skin that is regularly exposed to sunlight or other ultraviolet radiation. The earliest form of ... skin cancer is to reduce your exposure to sunlight . Always use sunscreen: Apply sunscreen with sun protection ...

  9. Components of skin

    MedlinePlus Videos and Cool Tools

    ... skin layers from the outside environment and contains cells that make keratin, a substance that waterproofs and strengthens the skin. The epidermis also has cells that contain melanin, the dark pigment that gives ...

  10. Skin, Hair, and Nails

    MedlinePlus

    ... thousands of cells and hundreds of sweat glands, oil glands, nerve endings, and blood vessels. Skin is ... empty into hair follicles and pores, produce the oil sebum that lubricates the skin and hair. Sebaceous ...

  11. Bleeding into the skin

    MedlinePlus

    Protect aging skin. Avoid trauma such as bumping or pulling on skin areas. For a cut or scrape, use direct pressure to stop the bleeding. If you have a drug reaction, ask your provider about stopping the drug. Otherwise, follow ...

  12. Bacterial Skin Infections

    MedlinePlus

    ... Diseases Take Big Slice Out of America's Health, Economy (News) Health Tip: Use Caution When Applying Hair Dye Additional ... Skin Diseases Take Big Slice Out of America's Health, Economy THURSDAY, March 2, 2017 (HealthDay News) -- Skin diseases ...

  13. Necrotizing Skin Infections

    MedlinePlus

    ... Diseases Take Big Slice Out of America's Health, Economy (News) Health Tip: Use Caution When Applying Hair Dye Additional ... Skin Diseases Take Big Slice Out of America's Health, Economy THURSDAY, March 2, 2017 (HealthDay News) -- Skin diseases ...

  14. Neuromodulators for Aging Skin

    MedlinePlus

    ... Stretch Marks Sun-damaged Skin Unwanted Hair Unwanted Tattoos Varicose Veins Vitiligo Wrinkles Treatments and Procedures Ambulatory ... Stretch Marks Sun-damaged Skin Unwanted Hair Unwanted Tattoos Varicose Veins Vitiligo Wrinkles Treatments and Procedures Ambulatory ...

  15. PPD skin test

    MedlinePlus

    ... is a method used to diagnose silent (latent) tuberculosis (TB) infection. PPD stands for purified protein derivative. ... skin test; Tuberculin skin test; Mantoux test Images Tuberculosis in the kidney Tuberculosis in the lung Positive ...

  16. Examine Your Skin

    MedlinePlus Videos and Cool Tools

    ... Store In Memory Melanoma Info Melanoma Facts Melanoma Prevention Sunscreen Suggestions Examine Your Skin Newly Diagnosed? Understanding ... video. UPDATED: November 23, 2016 Melanoma Facts Melanoma Prevention Sunscreen Suggestions Examine Your Skin Newly Diagnosed? Understanding ...

  17. Microarray analysis of microRNA expression in mouse fetus at 13.5 and 14.5 days post-coitum in ear and back skin tissues.

    PubMed

    Torres, Leda; Juárez, Ulises; García, Laura; Miranda-Ríos, Juan; Frias, Sara

    2016-09-01

    There is no information regarding the role of microRNAs in the development of the external ear in mammals. The purpose of this study was to determine the stage-specific expression of microRNA during external ear development in mice under normal conditions. GeneChip miRNA 3.0 arrays by Affymetrix were used to obtain miRNA expression profiles from mice fetal pinnae and back skin tissues at 13.5 days-post-coitum (dpc) and 14.5 dpc. Biological triplicates for each tissue were analyzed; one litter represents one biological replica, each litter had 16 fetuses on average. The results were analyzed with Affymetrix's Transcriptome Analysis Console software to identify differentially expressed miRNAs. The inquiry showed significant differential expression of 25 miRNAs at 13.5 dpc and 31 at 14.5 dpc, some of these miRNAs were predicted to target genes implicated in external ear development. One example is mmu-miR-10a whose low expression in pinnae is known to impact ear development by modulating Hoxa1 mRNA levels Garzon et al. (2006), Gavalas et al. (1998) [1], [2]. Other findings like the upregulation of mmu-miR-200c and mmu-miR-205 in the pinnae tissues of healthy mice are in agreement with what has been reported in human patients with microtia, in which down regulation of both miRNAs has been found Li et al. (2013) [3]. This study uncovered a spatiotemporal pattern of miRNA expression in the external ear, which results from continuous transcriptional changes during normal development of body structures. All microarray data are available at the Gene Expression Omnibus (GEO) at NCBI under accession number GSE64945.

  18. Ultrasound skin imaging.

    PubMed

    Alfageme Roldán, F

    2014-12-01

    The interaction of high-frequency ultrasound waves with the skin provides the basis for noninvasive, fast, and accessible diagnostic imaging. This tool is increasingly used in skin cancer and inflammatory conditions as well as in cosmetic dermatology. This article reviews the basic principles of skin ultrasound and its applications in the different areas of dermatology.

  19. Skin self-exam

    MedlinePlus

    Skin cancer - self-exam; Melanoma - self-exam; Basal cell cancer - self-exam; Squamous cell - self-exam; Skin mole - self-exam ... Cancer Institute. What You Need To Know About Melanoma and Other Skin Cancers: How To Check Your ...

  20. Psychoneuroimmunology and the Skin.

    PubMed

    Honeyman, Juan F

    2016-08-23

    The nervous, immune, endocrine and integumentary systems are closely related and interact in a number of normal and pathological conditions. Nervous system mediators may bring about direct changes to the skin or may induce the release of immunological or hormonal mediators that cause pathological changes to the skin. This article reviews the psychological mechanisms involved in the development of skin diseases.

  1. Biology of Skin Color.

    ERIC Educational Resources Information Center

    Corcos, Alain

    1983-01-01

    Information from scientific journals on the biology of skin color is discussed. Major areas addressed include: (1) biology of melanin, melanocytes, and melanosomes; (2) melanosome and human diversity; (3) genetics of skin color; and (4) skin color, geography, and natural selection. (JN)

  2. The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

    PubMed Central

    Naguib, Youssef W.; Kumar, Amit; Cui, Zhengrong

    2014-01-01

    Topical 5-fluorouracil (5-FU) is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter). In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5%) was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy. PMID:25313350

  3. Anyone Can Get Skin Cancer

    Cancer.gov

    No matter if your skin is light, dark, or somewhere in between, everyone is at risk for skin cancer. Learn what skin cancer looks like, how to find it early, and how to lower the chance of skin cancer.

  4. Identification of a novel skin penetration enhancement peptide by phage display peptide library screening.

    PubMed

    Kumar, Sunny; Sahdev, Preety; Perumal, Omathanu; Tummala, Hemachand

    2012-05-07

    Skin is an important site for local or systemic application of drugs. However, a majority of drugs have poor permeability through the skin's topmost layer, stratum corneum (SC). The aim of this study was to identify safe and smaller peptides that could enhance the skin penetration of drug molecules. By screening phage display peptide library, we have identified a T2 peptide (LVGVFH), which enhanced the penetration of bacteriophages (~800 nm long bacterial viruses) across porcine and mouse skin. Pretreating the skin with synthetic T2 peptide at pH 4.5 resulted in significant penetration enhancement of hydrophilic drug 5-fluorouracil (5-FU) across skin. FTIR spectroscopy showed that the T2 peptide interacted with skin lipids to enhance the skin penetration. Pretreating the skin with T2 peptide enhanced the partitioning of small molecules with different lipophilicities (5-FU, fluorescein isothiocyanate, and rhodamine 123 hydrochloride) into skin. Fluorescence studies showed that T2 peptide enhanced the diffusion of these molecules into intercellular lipids of SC and thus enhanced the penetration into the skin. Histidine at the c-terminus of T2 peptide was identified to be critical for the skin penetration enhancement. T2 peptide interacted with skin lipids to cause skin penetration enhancement. The study identified a novel, safe, and noninvasive peptide to improve the skin penetration of drugs without chemical conjugation.

  5. Sensitive skin: an overview.

    PubMed

    Inamadar, Arun C; Palit, Aparna

    2013-01-01

    Sensitive skin is less tolerant to frequent and prolonged use of cosmetics and toiletries. It is self-diagnosed and typically unaccompanied by any obvious physical signs of irritation. With the change in lifestyle and also with increased opportunity to use many new brands of cosmetics and toiletries, there has been an increase in females complaining of unique sensation in their facial skin. Sensitive skin presents as smarting, burning, stinging, itching, and/or tight sensation in their facial skin. The condition is found in more than 50% of women and 40% of men, creating a sizable demand for products designed to minimize skin sensitivity. Good numbers of invasive and non-invasive tests are designed to evaluate and predict the sensitive skin. Management includes guidelines for selecting suitable cosmetics and toiletries in sensitive skin individuals.

  6. Pursuing prosthetic electronic skin

    NASA Astrophysics Data System (ADS)

    Chortos, Alex; Liu, Jia; Bao, Zhenan

    2016-09-01

    Skin plays an important role in mediating our interactions with the world. Recreating the properties of skin using electronic devices could have profound implications for prosthetics and medicine. The pursuit of artificial skin has inspired innovations in materials to imitate skin's unique characteristics, including mechanical durability and stretchability, biodegradability, and the ability to measure a diversity of complex sensations over large areas. New materials and fabrication strategies are being developed to make mechanically compliant and multifunctional skin-like electronics, and improve brain/machine interfaces that enable transmission of the skin's signals into the body. This Review will cover materials and devices designed for mimicking the skin's ability to sense and generate biomimetic signals.

  7. [Skin diseases and obesity].

    PubMed

    Guerra-Segovia, Carolina; Ocampo-Candiani, Jorge

    2015-01-01

    Obesity is a public health problem worldwide. It predominates in industrialized countries; however, it is prevalent in all nations. It is defined as a condition of excess adipose tissue and is the result of changes in lifestyle, excessive consumption of energy-dense foods with poor nutritional value, physical inactivity and the reduction of open space where one can practice a sport. Although obesity is associated with multiple diseases, it is important to stress that the metabolic changes caused by it affect skin physiology and play a predisposing factor for the development of skin diseases. Very little has been studied on the impact of obesity on the skin. The purpose of this article is to review the most frequently skin diseases in obesity. Some skin pathologies in obesity are caused by changes in skin physiology, others are related to insulin resistance or constitute an exacerbating factor for dermatitis. This article covers the clinical features of obesity related skin disease and its management.

  8. Antigen-Presenting Cells in the Skin.

    PubMed

    Kashem, Sakeen W; Haniffa, Muzlifah; Kaplan, Daniel H

    2017-02-06

    Professional antigen-presenting cells (APCs) in the skin include dendritic cells, monocytes, and macrophages. They are highly dynamic, with the capacity to enter skin from the peripheral circulation, patrol within tissue, and migrate through lymphatics to draining lymph nodes. Skin APCs are endowed with antigen sensing, processing, and presenting machinery and play key roles in initiating, modulating, and resolving cutaneous inflammation. Skin APCs are a highly heterogeneous population with functionally specialized subsets that are developmentally imprinted and modulated by local tissue microenvironmental and inflammatory cues. This review explores recent advances that have allowed for a more accurate taxonomy of APC subsets found in both mouse and human skin. It also examines the functional specificity of individual APC subsets and their collaboration with other immune cell types that together promote adaptive T cell and regional cutaneous immune responses during homeostasis, inflammation, and disease. Expected final online publication date for the Annual Review of Immunology Volume 35 is April 26, 2017 . Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  9. Wrist Hypothermia Related to Continuous Work with a Computer Mouse: A Digital Infrared Imaging Pilot Study.

    PubMed

    Reste, Jelena; Zvagule, Tija; Kurjane, Natalja; Martinsone, Zanna; Martinsone, Inese; Seile, Anita; Vanadzins, Ivars

    2015-08-07

    Computer work is characterized by sedentary static workload with low-intensity energy metabolism. The aim of our study was to evaluate the dynamics of skin surface temperature in the hand during prolonged computer mouse work under different ergonomic setups. Digital infrared imaging of the right forearm and wrist was performed during three hours of continuous computer work (measured at the start and every 15 minutes thereafter) in a laboratory with controlled ambient conditions. Four people participated in the study. Three different ergonomic computer mouse setups were tested on three different days (horizontal computer mouse without mouse pad; horizontal computer mouse with mouse pad and padded wrist support; vertical computer mouse without mouse pad). The study revealed a significantly strong negative correlation between the temperature of the dorsal surface of the wrist and time spent working with a computer mouse. Hand skin temperature decreased markedly after one hour of continuous computer mouse work. Vertical computer mouse work preserved more stable and higher temperatures of the wrist (>30 °C), while continuous use of a horizontal mouse for more than two hours caused an extremely low temperature (<28 °C) in distal parts of the hand. The preliminary observational findings indicate the significant effect of the duration and ergonomics of computer mouse work on the development of hand hypothermia.

  10. Wrist Hypothermia Related to Continuous Work with a Computer Mouse: A Digital Infrared Imaging Pilot Study

    PubMed Central

    Reste, Jelena; Zvagule, Tija; Kurjane, Natalja; Martinsone, Zanna; Martinsone, Inese; Seile, Anita; Vanadzins, Ivars

    2015-01-01

    Computer work is characterized by sedentary static workload with low-intensity energy metabolism. The aim of our study was to evaluate the dynamics of skin surface temperature in the hand during prolonged computer mouse work under different ergonomic setups. Digital infrared imaging of the right forearm and wrist was performed during three hours of continuous computer work (measured at the start and every 15 minutes thereafter) in a laboratory with controlled ambient conditions. Four people participated in the study. Three different ergonomic computer mouse setups were tested on three different days (horizontal computer mouse without mouse pad; horizontal computer mouse with mouse pad and padded wrist support; vertical computer mouse without mouse pad). The study revealed a significantly strong negative correlation between the temperature of the dorsal surface of the wrist and time spent working with a computer mouse. Hand skin temperature decreased markedly after one hour of continuous computer mouse work. Vertical computer mouse work preserved more stable and higher temperatures of the wrist (>30 °C), while continuous use of a horizontal mouse for more than two hours caused an extremely low temperature (<28 °C) in distal parts of the hand. The preliminary observational findings indicate the significant effect of the duration and ergonomics of computer mouse work on the development of hand hypothermia. PMID:26262633

  11. Multistage skin tumor promotion: involvement of a protein kinase

    SciTech Connect

    Mamrack, M.; Slaga, T. J.

    1980-01-01

    Current information suggests that chemical carcinogenesis is a multistep process with one of the best studied models in this regard being the two-stage carcinogenesis system using mouse skin. The effects of several carcinogens and tumor promoters in various sequences of application were studied to examine the nature of the process. The actions of several tumor inhibitors were compared. (ACR)

  12. Netherton syndrome: defective kallikrein inhibition in the skin leads to skin inflammation and allergy.

    PubMed

    Furio, Laetitia; Hovnanian, Alain

    2014-09-01

    Netherton syndrome (NS) is an orphan genetic skin disease with a profound skin barrier defect and severe allergic manifestations. NS is caused by loss of function mutations in SPINK5 encoding lympho-epithelial Kazal-type inhibitor (LEKTI), a secreted multi-domain serine protease inhibitor expressed in stratified epithelia. Studies in mouse models and in NS patients have established that unopposed kallikrein 5 activity triggers stratum corneum detachment and activates PAR-2 signaling, leading to the autonomous production of pro-allergic and pro-inflammatory mediators. This emerging knowledge on NS pathogenesis has highlighted a central role for protease regulation in skin homeostasis but also in the complexity of the disease, and holds the promise of new specific treatments.

  13. Skin protection for hairdressers.

    PubMed

    Skudlik, Christoph; John, Swen Malte

    2007-01-01

    The application of protective creams in the hairdressing trade forms part of a complex concept for the prevention of occupational skin disorders. To date, no comparative controlled intervention studies have been carried out using different skin-protective creams. Previously published skin protection plans concerning barrier creams for the hairdressing trade are fairly general or rudimentary, reflecting our still limited knowledge on the subject. Bioengineering studies have even demonstrated a paradoxical effect of a certain skin-protective foam designed for hairdressers. Regarding other barrier creams, a certain protective effect could however be shown in studies concerning exposure to wetness and detergents. Pre-exposition skin protection seems to be of particular relevance. Thus, in principle, the regular application of adequate skin protection creams can be recommended in the hairdressing trade, although the protective effect should not be overvalued.

  14. Neuroendocrinology of the skin

    PubMed Central

    Zmijewski, Michal A

    2011-01-01

    The concept on the skin neuro-endocrine has been formulated ten years ago, and recent advances in the field further strengthened this role. Thus, skin forms a bidirectional platform for a signal exchange with other peripheral organs, endocrine and immune systems or brain to enable rapid and selective responses to the environment in order to maintain local and systemic homeostasis. In this context, it is not surprising that the function of the skin is tightly regulated by systemic neuro-endocrine system. Skin cells and skin appendages not only respond to neuropeptides, steroids and other regulatory signals, but also actively synthesis variety of hormones. The stress responses within the skin are tightly regulated by locally synthesized factors and their receptor expression. There is growing evidence for alternative splicing playing an important role in stress signaling. Deregulation of the skin neuro-endocrine signaling can lead or/and be a marker of variety of skin diseases. The major problem in this area relates to their detailed mechanisms of crosstalk between skin and brain and between the local and global endocrine as well as immune systems. PMID:21519402

  15. Skin care and incontinence

    MedlinePlus

    Incontinence - skin care; Incontinence - pressure sore; Incontinence - pressure ulcer ... redness, peeling, irritation, and yeast infections likely. Bedsores ( pressure sores ) may also develop if the person: Has ...

  16. IMQ Induced K14-VEGF Mouse: A Stable and Long-Term Mouse Model of Psoriasis-Like Inflammation

    PubMed Central

    Wang, Xuguo; Sun, Jun; Hu, JinHong

    2015-01-01

    An imiquimod (IMQ) induced wild type (WT) mouse can mimic some features of psoriasis, such as thickened skin, abnormal keratinocyte-related proteins, infiltration of inflammatory cells and pro-inflammatory cytokines. This model is a prevalent model that is widely used in the study of psoriasis. However, skin inflammation decreases during the eighth day when IMQ is given to WT mice, which may result in false results when evaluating the pharmacodynamics effects of a drug. To extend the timeliness and inherit the advantages of this model, we applied IMQ to the skin of 8-week-old homozygous K14-VEGF mice to investigate whether IMQ can prolong mice ear inflammation. In our experiments, we found that, compared to the IMQ induced WT mice model, the IMQ induced K14-VEGF mice have serious skin inflammation, even on the fourteenth day. We also evaluated the stability of skin inflammation at days 8, 10, and 13, and the inflammatory situation remained stable in the skin. This research intends to improve the existing model, and we hypothesize that the IMQ induced K14-VEGF mouse will become a practical mouse model in psoriasis research. PMID:26691862

  17. Physiology of skin.

    PubMed

    Greaves, M W

    1976-07-01

    One of Montagna's greatest contributions to study of the biology of the skin has been his demolition of the artificial walls that traditionally separated the histologist from the physiologist. He has shown that only by relating function with structure can we shed light on the workings of the skin. He has stressed the fallacy of studying a single structural or functional unit in isolation from others. The skin represents an organization of many different functional units, and physiology of skin is the study of this organization. My purpose is to make a personal commentary on the achievements, failures, and prospects of understanding some aspects of the organization of the functional units. Twenty-five years ago, the importance of relating skin to internal organs and systems received much attention. We have long been aware that skin sometimes reacts to internal disease, but only recently has the impact of skin disorders on the circulatory, renal, and gastrointestinal systems been recognized. As a result, our patients are now less likely to suffer from neglect of the whole which follows narrow over-specialized attention to the part. Increased interest in endocrine effects on the skin has revealed that several important physiologic activities of the skin are either partly or wholly regulated by hormones secreted by endocrine glands. Nevertheless, some physiologic activities in skin seems to be independent, their regulation being carried out by local mediating hormones. Other activities involve both central and local regulation. The nature and roles of these two control mechanisms and their interrelation constitute by far the most promising physiologic research in skin.

  18. About Skin: Your Body's Largest Organ

    MedlinePlus

    ... your skin, hair, and nails Skin dictionary Camp Discovery Good Skin Knowledge lesson plans and activities Video library Find a ... your skin, hair, and nails Skin dictionary Camp Discovery Good Skin Knowledge lesson plans and activities Video library Find a ...

  19. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation.

    PubMed

    Li, Wenjuan; Zhang, Chunjing; Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis.

  20. Blue light-induced oxidative stress in live skin.

    PubMed

    Nakashima, Yuya; Ohta, Shigeo; Wolf, Alexander M

    2017-03-15

    Skin damage from exposure to sunlight induces aging-like changes in appearance and is attributed to the ultraviolet (UV) component of light. Photosensitized production of reactive oxygen species (ROS) by UVA light is widely accepted to contribute to skin damage and carcinogenesis, but visible light is thought not to do so. Using mice expressing redox-sensitive GFP to detect ROS, blue light could produce oxidative stress in live skin. Blue light induced oxidative stress preferentially in mitochondria, but green, red, far red or infrared light did not. Blue light-induced oxidative stress was also detected in cultured human keratinocytes, but the per photon efficacy was only 25% of UVA in human keratinocyte mitochondria, compared to 68% of UVA in mouse skin. Skin autofluorescence was reduced by blue light, suggesting flavins are the photosensitizer. Exposing human skin to the blue light contained in sunlight depressed flavin autofluorescence, demonstrating that the visible component of sunlight has a physiologically significant effect on human skin. The ROS produced by blue light is probably superoxide, but not singlet oxygen. These results suggest that blue light contributes to skin aging similar to UVA.

  1. Biothermomechanics of skin tissues

    NASA Astrophysics Data System (ADS)

    Xu, F.; Lu, T. J.; Seffen, K. A.

    Biothermomechanics of skin is highly interdisciplinary involving bioheat transfer, burn damage, biomechanics and neurophysiology. During heating, thermally induced mechanical stress arises due to the thermal denaturation of collagen, resulting in macroscale shrinkage. Thus, the strain, stress, temperature and thermal pain/damage are highly correlated; in other words, the problem is fully coupled. The aim of this study is to develop a computational approach to examine the heat transfer process and the heat-induced mechanical response, so that the differences among the clinically applied heating modalities can be quantified. Exact solutions for temperature, thermal damage and thermal stress for a single-layer skin model were first derived for different boundary conditions. For multilayer models, numerical simulations using the finite difference method (FDM) and finite element method (FEM) were used to analyze the temperature, burn damage and thermal stress distributions in the skin tissue. The results showed that the thermomechanical behavior of skin tissue is very complex: blood perfusion has little effect on thermal damage but large influence on skin temperature distribution, which, in turn, influences significantly the resulting thermal stress field; the stratum corneum layer, although very thin, has a large effect on the thermomechanical behavior of skin, suggesting that it should be properly accounted for in the modeling of skin thermal stresses; the stress caused by non-uniform temperature distribution in the skin may also contribute to the thermal pain sensation.

  2. Sun on Skin.

    ERIC Educational Resources Information Center

    Collins, Margaret

    1998-01-01

    Describes sessions in two schools that focused on recent work with 2,857 children in Europe researching the children's perceptions of sun on skin. Investigates children's ideas about skin on different parts of the body, which was most vulnerable to the sun, and different types and colors. (Author/CCM)

  3. Quantification of quantum dot murine skin penetration with UVR barrier impairment

    PubMed Central

    Mortensen, Luke J.; Jatana, Samreen; Gelein, Robert; De Benedetto, Anna; De Mesy Bentley, Karen L.; Beck, Lisa; Elder, Alison; DeLouise, Lisa A.

    2013-01-01

    Ultraviolet radiation (UVR) skin exposure is a common exogenous insult that can alter skin barrier and immune functions. With the growing presence of nanoparticles (NPs) in consumer goods and technological applications the potential for NPs to contact UVR exposed skin is increasing. Therefore it is important to understand the effect of UVR on NP skin penetration and potential for systemic translocation. Previous studies qualitatively showed that UVR skin exposure can increase the penetration of NPs below the stratum corneum. In the present work, an in vivo mouse model was used to quantitatively examine the skin penetration of carboxylated (CdSe/ZnS, core/shell) quantum dots (QDs) through intact and UVR barrier disrupted murine skin by organ Cd mass analysis. Transepidermal water loss was used to measure the magnitude of the skin barrier defect as a function of dose and time post UVR exposure. QDs were applied to mice 3-4 days post UVR exposure at the peak of the skin barrier disruption. Our results reveal unexpected trends that suggest these negative charged QDs can penetrate barrier intact skin and that penetration and systemic transport depends on the QD application time post UVR exposure. The effect of UVR on skin resident dendritic cells and their role in the systemic translocation of these QDs are described. Our results suggest that NP skin penetration and translocation may depend on the specific barrier insult and the inflammatory status of the skin. PMID:23078247

  4. Postmenopausal skin and estrogen.

    PubMed

    Archer, David F

    2012-10-01

    The aging global population continues to drive increasing demand for cosmaceuticals and cosmetic surgery among older men and women. Since the discovery in the 1990s that estrogen receptors are present in skin cells and decline in number from the onset of menopause in women, researchers have explored a number of ways in which estrogen can improve skin condition. Skin is estrogen responsive, and several studies now exist to support the antiaging properties of estrogen replacement therapies in postmenopausal women. Both systemic and topical estrogens appear to have positive effects on hormonal aging, increasing skin collagen content, thickness, elasticity and hydration. Estrogen therapies may also improve wound healing and reduce the incidence of wound complications. This review explores the potential for targeted estrogen replacement as a therapeutic option for long-term skin management in postmenopausal women.

  5. [Skin and sun exposure].

    PubMed

    Cannavò, Serafinella Patrizia; Borgia, Francesco; Trifirò, Caterina; Aragona, Emanuela

    2013-01-01

    Fisherman commonly experience a significant number of cutaneous problems, related to the exposure to environmental factors due to their working conditions. Among these factors, sun exposure is able to determine both acute and chronic skin damage, mostly linked to the effects of the ultraviolet (UV) radiation on epidermal and dermal structures. In particular, UV-A appears to play a major role in the deterioration of dermal structure leading to the photoaged appearance of the skin, while UV-B is mainly responsible for skin cancers. Peculiar clinical features of skin damage in fishermen include dryness, irregular pigmentation, wrinkling, stellate pseudoscars, elastosis, inelasticity, telangiectasia, comedones and sebaceous hyperplasia. Furtheremore, the high incidence of non-melanoma skin cancers, on sun-exposed areas, confirms the need for occupational health policies focusing on issues such as photoprotection.

  6. Diversification and specialization of touch receptors in skin.

    PubMed

    Owens, David M; Lumpkin, Ellen A

    2014-06-02

    Our skin is the furthest outpost of the nervous system and a primary sensor for harmful and innocuous external stimuli. As a multifunctional sensory organ, the skin manifests a diverse and highly specialized array of mechanosensitive neurons with complex terminals, or end organs, which are able to discriminate different sensory stimuli and encode this information for appropriate central processing. Historically, the basis for this diversity of sensory specializations has been poorly understood. In addition, the relationship between cutaneous mechanosensory afferents and resident skin cells, including keratinocytes, Merkel cells, and Schwann cells, during the development and function of tactile receptors has been poorly defined. In this article, we will discuss conserved tactile end organs in the epidermis and hair follicles, with a focus on recent advances in our understanding that have emerged from studies of mouse hairy skin.

  7. N-Nicotinoyl dopamine, a novel niacinamide derivative, retains high antioxidant activity and inhibits skin pigmentation.

    PubMed

    Kim, Bora; Kim, Jin Eun; Lee, Su Min; Lee, Soung-Hoon; Lee, Jin Won; Kim, Myung Kyoo; Lee, Kye Jong; Kim, Hyuk; Lee, Joo Dong; Choi, Kang-Yell

    2011-11-01

    We synthesized a novel derivative of a well-known skin-lightening compound niacinamide, N-nicotinoyl dopamine (NND). NND did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. However, NND retains high antioxidant activity without affecting viability of cells. In a reconstructed skin model, topical applications of 0.05% and 0.1% NND induced skin lightening and decreased melanin production without affecting the viability and morphology of melanocytes and overall tissue histology. Moreover, no evidence for skin irritation or sensitization was observed when 0.1% NND emulsion was applied onto the skin of 52 volunteers. The effect of NND on skin lightening was further revealed by pigmented spot analyses of human clinical trial. Overall, NND treatment may be a useful trial for skin lightening and treating pigmentary disorders.

  8. Surface proteins of Staphylococcus aureus play an important role in experimental skin infection.

    PubMed

    Kwiecinski, Jakub; Jin, Tao; Josefsson, Elisabet

    2014-12-01

    Staphylococcus aureus is the most common cause of skin infections that range from mild diseases up to life-threatening conditions. Mechanisms of S. aureus virulence in those infections remain poorly studied. To investigate the impact of S. aureus surface proteins on skin infection, we used mouse models of skin abscess formation and skin necrosis, induced by a subcutaneous injection of bacteria. In the skin abscess model, a sortase-deficient S. aureus strain lacking all of its cell-wall anchored proteins was less virulent than its wild-type strain. Also, strains specifically lacking protein A, fibronecting binding proteins, clumping factor A or surface protein SasF were impaired in their virulence. When a model of dermonecrosis was studied, the S. aureus surface proteins could not be shown to be involved. In summary, surface proteins play an important role in virulence of S. aureus skin abscess infections, but not in formation of skin necrosis.

  9. 6 Common Cancers - Skin Cancer

    MedlinePlus

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Skin Cancer Past Issues / Spring 2007 Table of Contents For ... AP Photo/Herald-Mail, Kevin G. Gilbert Skin Cancer Skin cancer is the most common form of ...

  10. Urostomy - stoma and skin care

    MedlinePlus

    ... gov/ency/patientinstructions/000477.htm Urostomy - stoma and skin care To use the sharing features on this ... stoma if it is scraped. Caring for the Skin Around Your Stoma After surgery, the skin around ...

  11. Archaea on Human Skin

    PubMed Central

    Probst, Alexander J.; Auerbach, Anna K.; Moissl-Eichinger, Christine

    2013-01-01

    The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin. PMID:23776475

  12. Skin and antioxidants.

    PubMed

    Poljsak, Borut; Dahmane, Raja; Godic, Aleksandar

    2013-04-01

    It is estimated that total sun exposure occurs non-intentionally in three quarters of our lifetimes. Our skin is exposed to majority of UV radiation during outdoor activities, e.g. walking, practicing sports, running, hiking, etc. and not when we are intentionally exposed to the sun on the beach. We rarely use sunscreens during those activities, or at least not as much and as regular as we should and are commonly prone to acute and chronic sun damage of the skin. The only protection of our skin is endogenous (synthesis of melanin and enzymatic antioxidants) and exogenous (antioxidants, which we consume from the food, like vitamins A, C, E, etc.). UV-induced photoaging of the skin becomes clinically evident with age, when endogenous antioxidative mechanisms and repair processes are not effective any more and actinic damage to the skin prevails. At this point it would be reasonable to ingest additional antioxidants and/or to apply them on the skin in topical preparations. We review endogenous and exogenous skin protection with antioxidants.

  13. Archaea on human skin.

    PubMed

    Probst, Alexander J; Auerbach, Anna K; Moissl-Eichinger, Christine

    2013-01-01

    The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin.

  14. Sensitive skin: an overview.

    PubMed

    Berardesca, E; Farage, M; Maibach, H

    2013-02-01

    Sensitive skin is a condition of subjective cutaneous hyper-reactivity to environmental factors. Subjects experiencing this condition report exaggerated reactions when their skin is in contact with cosmetics, soaps and sun screens, and they often report worsening after exposure to dry and cold climate. Although no sign of irritation is commonly detected, itching, burning, stinging and a tight sensation are constantly present. Generally substances that are not commonly considered irritants are involved in this abnormal response.Sensitive skin and subjective irritation are widespread but still far from being completely defined and understood. A correlation between sensitive skin and constitutional anomalies and/or other triggering factors such as occupational skin diseases or chronic exposure to irritants has been hypothesized. Recent findings suggest that higher sensitivity can be due to different mechanisms. Hyper-reactors may have a thinner stratum corneum with a reduced corneocyte area causing a higher transcutaneous penetration of water-soluble chemicals. Alterations in vanilloid receptors and changes in neuronal transmission have been described. Monitoring skin parameters such as barrier function, proclivity to irritation, corneocyte size and sensorial transmission can also be useful to identify regional differences in skin sensitivity.

  15. The Ontogeny of Skin

    PubMed Central

    Visscher, Marty; Narendran, Vivek

    2014-01-01

    Significance: During gestation, fetal skin progresses from a single layer derived from ectoderm to a complex, multi-layer tissue with the stratum corneum (SC) as the outermost layer. Innate immunity is a conferred complex process involving a balance of pro- and anti-inflammatory cytokines, structural proteins, and specific antigen-presenting cells. The SC is a part of the innate immune system as an impermeable physical barrier containing anti-microbial lipids and host defense proteins. Postnatally, the epidermis continually replenishes itself, provides a protective barrier, and repairs injuries. Recent Advances: Vernix caseosa protects the fetus during gestation and facilitates development of the SC in the aqueous uterine environment. The anti-infective, hydrating, acidification, and wound-healing properties post birth provide insights for the development of strategies that facilitate SC maturation and repair in the premature infant. Critical Issues: Reduction of infant mortality is a global health priority. Premature infants have an incompetent skin barrier putting them at risk for irritant exposure, skin compromise and life-threatening infections. Effective interventions to accelerate skin barrier maturation are compelling. Future Directions: Investigations to determine the ontogeny of barrier maturation, that is, SC structure, composition, cohesiveness, permeability, susceptibility to injury, and microflora, as a function of gestational age are essential. Clinicians need to know when the premature skin barrier becomes fully competent and comparable to healthy newborn skin. This will guide the development of innovative strategies for optimizing skin barrier development. PMID:24761361

  16. Environment and the skin

    PubMed Central

    Suskind, Raymond R.

    1977-01-01

    The skin is an important interface between man and his environment; it is an important portal of entry for hazardous agents and a vulnerable target tissue as well. It is a uniquely accessible model system for detecting hazards and for studying mechanisms of a wide variety of biologic funcitons. Environmental causes of skin reactions comprise a vast array of physical, chemical and biological agents. To appreciate the role of the skin as an interface with man's environment, it is necessary to understand the multiple adaptive mechanisms, and the defenses of the skin against the environmental stresses. The skin is endowed with a versatile group of defenses against penetration, fluid loss from the body, thermal stress, solar radiation, physical trauma and microbial agents. Patterns of adverse response range in quality and intensity from uncomplicated itching to metastatic neoplasia. Environmental problems comprise a large segment of disabling skin disease. Although critical epidemiologic data is limited, cutaneous illnesses comprise a significant segment of occupational disease. This represents a significant loss in productivity and a major cause of disability. The most serious research needs include the development of surveillance systems for identifying skin hazards and determining frequency of environmental skin disease; the development of new models for studying cutaneous penetration; the elucidation of the mechanisms of nonallergic inflammatory reactions (primary irritation) and of the accommodation phenomenon; the development of more sensitive models for predicting adverse responses to marginal irritants; the utilization of modern skills of immunobiology and immunochemistry to elucidate mechanisms of allergic responses; the launching of epidemiologic studies to determine the long term effects of PCBs and associated compounds such as dioxins; and the expansion of research in the mechanisms of skin cancer in relation to susceptibility, genetic and metabolic

  17. Enhancement of hidden structures of early skin fibrosis using polarization degree patterns and Pearson correlation analysis.

    PubMed

    Sviridov, Alexander P; Chernomordik, Victor; Hassan, Moinuddin; Boccara, Albert C; Russo, Angelo; Smith, Paul; Gandjbakhche, Amir

    2005-01-01

    The skin of athymic nude mice is irradiated with a single dose of x-ray irradiation that initiated fibrosis. Digital photographs of the irradiated mice are taken by illuminating the mouse skin with linearly polarized probe light of 650 nm. The specific pattern of the surface distribution of the degree of polarization enables the detection of initial skin fibrosis structures that were not visually apparent. Data processing of the raw spatial distributions of the degree of polarization based on Fourier filtering of the high-frequency noise improves subjective perception of the revealed structure in the images. In addition, Pearson correlation analysis provides information about skin structural size and directionality.

  18. Cell Autonomous and Non-autonomous Effects of Senescent Cells in the Skin

    PubMed Central

    Demaria, Marco; Desprez, Pierre Yves; Campisi, Judith; Velarde, Michael C.

    2015-01-01

    Human and mouse skin accumulate senescent cells in both the epidermis and dermis during aging. When chronically present, senescent cells are thought to enhance the age-dependent deterioration of the skin during extrinsic and intrinsic aging. However, when transiently present, senescent cells promote optimal wound healing. Here, we review recent studies on how senescent cells and the senescence-associated secretory phenotype (SASP) contribute to different physiological and pathophysiological conditions in the skin with a focus on some of the cell autonomous and non-autonomous functions of senescent cells in the context of skin aging and wound healing. PMID:25855157

  19. Quantitative analysis on collagen morphology in aging skin based on multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Wu, Shulian; Li, Hui; Yang, Hongqin; Zhang, Xiaoman; Li, Zhifang; Xu, Shufei

    2011-04-01

    Multiphoton microscopy was employed for monitoring the structure changes of mouse dermis collagen in the intrinsic- or the extrinsic-age-related processes in vivo. The characteristics of textures in different aging skins were uncovered by fast Fourier transform in which the orientation index and bundle packing of collagen were quantitatively analyzed. Some significant differences in collagen-related changes are found in different aging skins, which can be good indicators for the statuses of aging skins. The results are valuable to the study of aging skin and also of interest to biomedical photonics.

  20. Mouse Curve Biometrics

    SciTech Connect

    Schulz, Douglas A.

    2007-10-08

    A biometric system suitable for validating user identity using only mouse movements and no specialized equipment is presented. Mouse curves (mouse movements with little or no pause between them) are individually classied and used to develop classication histograms, which are representative of an individual's typical mouse use. These classication histograms can then be compared to validate identity. This classication approach is suitable for providing continuous identity validation during an entire user session.

  1. Thermal Skin fabrication technology

    NASA Technical Reports Server (NTRS)

    Milam, T. B.

    1972-01-01

    Advanced fabrication techniques applicable to Thermal Skin structures were investigated, including: (1) chemical machining; (2) braze bonding; (3) diffusion bonding; and (4) electron beam welding. Materials investigated were nickel and nickel alloys. Sample Thermal Skin panels were manufactured using the advanced fabrication techniques studied and were structurally tested. Results of the program included: (1) development of improved chemical machining processes for nickel and several nickel alloys; (2) identification of design geometry limits; (3) identification of diffusion bonding requirements; (4) development of a unique diffusion bonding tool; (5) identification of electron beam welding limits; and (6) identification of structural properties of Thermal Skin material.

  2. Eicosanoids in skin inflammation.

    PubMed

    Nicolaou, Anna

    2013-01-01

    Eicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues.

  3. Building a Brainier Mouse.

    ERIC Educational Resources Information Center

    Tsien, Joe Z.

    2000-01-01

    Describes a genetic engineering project to build an intelligent mouse. Cites understanding the molecular basis of learning and memory as a very important step. Concludes that while science will never create a genius mouse that plays the stock market, it can turn a mouse into a quick learner with a better memory. (YDS)

  4. Animal models of skin disease for drug discovery

    PubMed Central

    Avci, Pinar; Sadasivam, Magesh; Gupta, Asheesh; De Melo, Wanessa CMA; Huang, Ying-Ying; Yin, Rui; Rakkiyappan, Chandran; Kumar, Raj; Otufowora, Ayodeji; Nyame, Theodore; Hamblin, Michael R

    2013-01-01

    Introduction Discovery of novel drugs, treatments, and testing of consumer products in the field of dermatology is a multi-billion dollar business. Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging, and hair loss, this is a very active field. Areas covered In this paper, we will cover the use of animal models that have been reported to recapitulate to a greater or lesser extent the features of human dermatological disease. There has been a remarkable increase in the number and variety of transgenic mouse models in recent years, and the basic strategy for constructing them is outlined. Expert opinion Inflammatory and autoimmune skin diseases are all represented by a range of mouse models both transgenic and normal. Skin cancer is mainly studied in mice and fish. Wound healing is studied in a wider range of animal species, and skin infections such as acne and leprosy also have been studied in animal models. Moving to the more consumer-oriented area of dermatology, there are models for studying the harmful effect of sunlight on the skin, and testing of sunscreens, and several different animal models of hair loss or alopecia. PMID:23293893

  5. Beyond the scalpel: targeting hedgehog in skin cancer prevention.

    PubMed

    Rudin, Charles M

    2010-01-01

    This perspective places the article by Tang et al. in this issue of the journal (beginning on page 25) in the context of recent work defining the hedgehog signaling pathway as a central etiologic factor and as a therapeutic target in basal cell cancer. Tang et al. show that inhibition of cyclooxygenase activity, either genetically (in a relevant mouse model) or pharmacologically (in the mouse and in patients highly predisposed to develop basal cell skin cancers), may suppress basal cell carcinogenesis. This new study of cyclooxygenase inhibition, together with recent data on the efficacy of hedgehog pathway inhibition, offers new hope for patients at a high risk for basal cell cancer.

  6. Skin, Hair, and Nails

    MedlinePlus

    ... and water, helps regulate body temperature through perspiration (sweating), and protects from the sun's damaging ultraviolet rays. ... skin contains thousands of cells and hundreds of sweat glands, oil glands, nerve endings, and blood vessels. ...

  7. Skin Cancer Screening

    MedlinePlus

    ... the body's largest organ . It protects against heat, sunlight, injury, and infection . Skin also helps control body ... cancer risk factors include: Being exposed to natural sunlight or artificial sunlight (such as from tanning beds) ...

  8. Skin Cancer Prevention

    MedlinePlus

    ... the body’s largest organ . It protects against heat, sunlight, injury, and infection . Skin also helps control body ... it is most common in areas exposed to sunlight, such as the face, neck, hands, and arms. ...

  9. Healthy Skin Matters

    MedlinePlus

    ... don’t offer a safe alternative to natural sunlight. Exposure to ultraviolet (UV ) (uhl-truh-VYE-uh- ... the exposure comes from tanning beds or natural sunlight. This damage increases the risk of skin cancer ...

  10. Aging changes in skin

    MedlinePlus

    ... sun exposure with areas that are protected from sunlight. Natural pigments seem to provide some protection against ... Exposures to industrial and household chemicals Indoor heating Sunlight can cause: Loss of elasticity (elastosis) Noncancerous skin ...

  11. Acral peeling skin syndrome.

    PubMed

    Hashimoto, K; Hamzavi, I; Tanaka, K; Shwayder, T

    2000-12-01

    Peeling skin syndrome is a rare autosomal recessive disease characterized by widespread painless peeling of the skin in superficial sheets. We describe a 34-year-old man with a lifelong history of spontaneous asymptomatic peeling skin limited to the acral surfaces. This patient probably represents a localized variant of peeling skin syndrome, which has previously been described as a generalized condition. Light and electron microscopic studies of biopsy specimens taken before and after immersion in water were performed. It was concluded that this patient has abnormal keratohyalin granules and inadequate aggregation of keratin filaments that caused the separation of the epidermis in the stratum corneum through the clear zone. Alternatively, unknown keratin species expressed in the clear zone may also cause the abnormality. (J Am Acad Dermatol 2000;43:1112-9.).

  12. Skin lesion KOH exam

    MedlinePlus

    ... is present. The fungus may be related to ringworm , athlete's foot , jock itch , or another fungal infection. ... foot Candida infection of the skin Jock itch Ringworm Ringworm of the body Review Date 4/14/ ...

  13. Allergy testing - skin

    MedlinePlus

    ... may order allergy skin tests if you have: Hay fever ( allergic rhinitis ) and asthma symptoms that are not ... team. Related MedlinePlus Health Topics Allergy Food Allergy Hay Fever Browse the Encyclopedia A.D.A.M., Inc. ...

  14. An elastic second skin

    NASA Astrophysics Data System (ADS)

    Yu, Betty; Kang, Soo-Young; Akthakul, Ariya; Ramadurai, Nithin; Pilkenton, Morgan; Patel, Alpesh; Nashat, Amir; Anderson, Daniel G.; Sakamoto, Fernanda H.; Gilchrest, Barbara A.; Anderson, R. Rox; Langer, Robert

    2016-08-01

    We report the synthesis and application of an elastic, wearable crosslinked polymer layer (XPL) that mimics the properties of normal, youthful skin. XPL is made of a tunable polysiloxane-based material that can be engineered with specific elasticity, contractility, adhesion, tensile strength and occlusivity. XPL can be topically applied, rapidly curing at the skin interface without the need for heat- or light-mediated activation. In a pilot human study, we examined the performance of a prototype XPL that has a tensile modulus matching normal skin responses at low strain (<40%), and that withstands elongations exceeding 250%, elastically recoiling with minimal strain-energy loss on repeated deformation. The application of XPL to the herniated lower eyelid fat pads of 12 subjects resulted in an average 2-grade decrease in herniation appearance in a 5-point severity scale. The XPL platform may offer advanced solutions to compromised skin barrier function, pharmaceutical delivery and wound dressings.

  15. Skin lesion removal

    MedlinePlus

    ... removal; Basal cell cancer - removal; Actinic keratosis - removal; Wart - removal; Squamous cell - removal; Mole - removal; Nevus - removal; ... can remove: Benign or pre-malignant skin lesions Warts Moles Sunspots Hair Small blood vessels in the ...

  16. Allergy Skin Tests

    MedlinePlus

    ... allergic rhinitis) Allergic asthma Dermatitis (eczema) Food allergies Penicillin allergy Bee venom allergy Latex allergy Skin tests are ... may recommend this test to check for an allergy to insect venom or penicillin. Patch test Patch testing is generally done to ...

  17. Skin tumors on squirrels

    USGS Publications Warehouse

    Herman, C.M.; Reilly, J.R.

    1955-01-01

    Skin tumors having the gross appearance of previously reported fibromas are reported on gray squirrels from N. Y., Md., Va., N. C., and W. Va. and from a fox squirrel from W. Va. and a porcupine from Pa.

  18. Genetics and skin aging

    PubMed Central

    Makrantonaki, Evgenia; Bekou, Vassiliki; Zouboulis, Christos C.

    2012-01-01

    Skin aging is a complex process and underlies multiple influences with the probable involvement of heritable and various environmental factors. Several theories have been conducted regarding the pathomechanisms of aged skin, however fundamental mechanisms still remain poorly understood. This article addresses the influence of genetics on skin aging and in particular deals with the differences observed in ethnic populations and between both genders. Recent studies indicate that male and female aged skin differs as far as the type, the consistency and the sensitivity to external factors is concerned. The same has been also documented between elderly people of different origin. Consequently, the aging process taking place in both genders and in diverse ethnic groups should be examined separately and products specialized to each population should be developed in order to satisfy the special needs. PMID:23467395

  19. Skin or nail culture

    MedlinePlus

    Mucosal culture; Culture - skin; Culture - mucosal; Nail culture; Culture - fingernail; Fingernail culture ... There, it is placed in a special dish (culture). It is then watched to see if bacteria, ...

  20. Skin Reactions to Cold

    PubMed Central

    Talpash, Orest

    1976-01-01

    Although skin reactions to cold are seen surprisingly infrequently in Canada, it is important to manage them correctly when they do occur. Frostbite, cold urticarias, Raynaud's disease and phenomenon, and several miscellaneous changes are discussed. PMID:21308019

  1. Chromophores in human skin

    NASA Astrophysics Data System (ADS)

    Young, Antony R.

    1997-05-01

    Human skin, especially the epidermis, contains several major solar ultraviolet-radiation- (UVR-) absorbing endogenous chromophores including DNA, urocanic acid, amino acids, melanins and their precursors and metabolites. The lack of solubility of melanins prevents their absorption spectra being defined by routine techniques. Indirect spectroscopic methods show that their spectral properties depend on the stimulus for melanogenesis. The photochemical consequences of UVR absorption by some epidermal chromophores are relatively well understood whereas we lack a detailed understanding of the consequent photobiological and clinical responses. Skin action spectroscopy is not a reliable way of relating a photobiological outcome to a specific chromophore but is important for UVR hazard assessment. Exogenous chromophores may be administered to the skin in combination with UVR exposure for therapeutic benefit, or as sunscreens for the prevention of sunburn and possibly skin cancer.

  2. Skin Diseases: Cross-section of human skin

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Cross-section of human skin Past Issues / Fall 2008 Table of Contents For ... Logical Images, Inc. I n the areas of skin health and skin diseases, the NIH's National Institute ...

  3. Photodynamic therapy improves the ultraviolet-irradiated hairless mice skin

    NASA Astrophysics Data System (ADS)

    Jorge, Ana Elisa S.; Hamblin, Michael R.; Parizotto, Nivaldo A.; Kurachi, Cristina; Bagnato, Vanderlei S.

    2014-03-01

    Chronic exposure to ultraviolet (UV) sunlight causes premature skin aging. In light of this fact, photodynamic therapy (PDT) is an emerging modality for treating cancer and other skin conditions, however its response on photoaged skin has not been fully illustrated by means of histopathology. For this reason, the aim of this study was analyze whether PDT can play a role on a mouse model of photoaging. Hence, SKH-1 hairless mice were randomly allocated in two groups, UV and UV/PDT. The mice were daily exposed to an UV light source (280-400 nm: peak at 350 nm) for 8 weeks followed by a single PDT session using 20% 5-aminolevulinic acid (ALA) topically. After the proper photosensitizer accumulation within the tissue, a non-coherent red (635 nm) light was performed and, after 14 days, skin samples were excised and processed for light microscopy, and their sections were stained with hematoxylin-eosin (HE) and Masson's Trichrome. As a result, we observed a substantial epidermal thickening and an improvement in dermal collagen density by deposition of new collagen fibers on UV/PDT group. These findings strongly indicate epidermal and dermal restoration, and consequently skin restoration. In conclusion, this study provides suitable evidences that PDT improves the UV-irradiated hairless mice skin, supporting this technique as an efficient treatment for photoaged skin.

  4. Dermocosmetics for dry skin: a new role for botanical extracts.

    PubMed

    Casetti, F; Wölfle, U; Gehring, W; Schempp, C M

    2011-01-01

    Dry skin is associated with a disturbed skin barrier and reduced formation of epidermal proteins and lipids. During recent years, skin-barrier-reinforcing properties of some botanical compounds have been described. Searching the PubMed database revealed 9 botanical extracts that specifically improve skin barrier and/or promote keratinocyte differentiation in vivo after topical application. The topical application of Aloe vera (leaf gel), Betula alba (birch bark extract), Helianthus annuus (sunflower oleodistillate), Hypericum perforatum (St. John's wort extract), Lithospermum erythrorhizon (root extract), Piptadenia colubrina (angico-branco extract) and Simarouba amara (bitter wood extract) increased skin hydration, reduced the transepidermal water loss, or promoted keratinocyte differentiation in humans in vivo. The topical application of Rubia cordifolia root extract and rose oil obtained from Rosa spp. flowers stimulated keratinocyte differentiation in mouse models. The underlying mechanisms of these effects are discussed. It is concluded that some botanical compounds display skin-barrier-reinforcing properties that may be used in dermocosmetics for dry skin. However, more investigations on the mode of action and more vehicle-controlled studies are required.

  5. Common Skin Cancers

    PubMed Central

    Ho, Vincent C.

    1992-01-01

    Melanoma, basal cell carcinoma, and squamous cell carcinoma are the three most common forms of skin cancer. The incidence of skin cancer is increasing at an alarming rate. Early detection is the key to successful management. In this article, the salient clinical features and diagnostic clues for these tumors and their precursor lesions are presented. Current management guidelines are also discussed. ImagesFigure 1Figures 2-3Figures 4-6Figures 7-9 PMID:21221380

  6. Nicotinamide and the skin.

    PubMed

    Chen, Andrew C; Damian, Diona L

    2014-08-01

    Nicotinamide, an amide form of vitamin B3, boosts cellular energy and regulates poly-ADP-ribose-polymerase 1, an enzyme with important roles in DNA repair and the expression of inflammatory cytokines. Nicotinamide shows promise for the treatment of a wide range of dermatological conditions, including autoimmune blistering disorders, acne, rosacea, ageing skin and atopic dermatitis. In particular, recent studies have also shown it to be a potential agent for reducing actinic keratoses and preventing skin cancers.

  7. Leishmania Skin Test

    DTIC Science & Technology

    2010-03-01

    Ninhydrin ), SDS-PAGE and non-viability testing . See Table 3 below: Table 3: Drug Substance Specifications Test Method Specification SDS-PAGE...AD_________________ Award Number: DAMD17-00-C-0030 TITLE: Leishmania Skin Test PRINCIPAL INVESTIGATOR: Nielsen, H.S., Jr...TYPE FINAL, PHASE II ADDENDUM 3. DATES COVERED (From - To) 1 APR 2009 - 28 FEB 2010 4. TITLE AND SUBTITLE Leishmania Skin Test 5a

  8. Rheumatologic Skin Disease.

    PubMed

    Kalus, Andrea

    2015-11-01

    In common rheumatologic diseases skin findings are an important diagnostic clue for astute clinicians. Skin manifestations can help identify systemic disease or may require therapy uniquely targeted at the cutaneous problem. This article discusses 3 common rheumatologic conditions seen in adults by dermatologists: cutaneous lupus, dermatomyositis, and morphea. The focus is on the cutaneous findings and clinical presentation. Some approaches to treatment are explored. Clues to help identify systemic disease are also highlighted.

  9. Ultraflexible organic photonic skin

    PubMed Central

    Yokota, Tomoyuki; Zalar, Peter; Kaltenbrunner, Martin; Jinno, Hiroaki; Matsuhisa, Naoji; Kitanosako, Hiroki; Tachibana, Yutaro; Yukita, Wakako; Koizumi, Mari; Someya, Takao

    2016-01-01

    Thin-film electronics intimately laminated onto the skin imperceptibly equip the human body with electronic components for health-monitoring and information technologies. When electronic devices are worn, the mechanical flexibility and/or stretchability of thin-film devices helps to minimize the stress and discomfort associated with wear because of their conformability and softness. For industrial applications, it is important to fabricate wearable devices using processing methods that maximize throughput and minimize cost. We demonstrate ultraflexible and conformable three-color, highly efficient polymer light-emitting diodes (PLEDs) and organic photodetectors (OPDs) to realize optoelectronic skins (oe-skins) that introduce multiple electronic functionalities such as sensing and displays on the surface of human skin. The total thickness of the devices, including the substrate and encapsulation layer, is only 3 μm, which is one order of magnitude thinner than the epidermal layer of human skin. By integrating green and red PLEDs with OPDs, we fabricate an ultraflexible reflective pulse oximeter. The device unobtrusively measures the oxygen concentration of blood when laminated on a finger. On-skin seven-segment digital displays and color indicators can visualize data directly on the body. PMID:27152354

  10. Role of pili in the adherence of Pseudomonas aeruginosa to mouse epidermal cells.

    PubMed Central

    Sato, H; Okinaga, K

    1987-01-01

    Pili have been demonstrated to be the adhesins of Pseudomonas aeruginosa for mouse epidermal cells. The mechanisms of adhesion of P. aeruginosa to mouse epidermal cells was studied by using four mutants derived from a single strain: flagellated and piliated (F+P+), flagellated and nonpiliated (F+P-), nonflagellated and piliated (F-P+), and nonflagellated and nonpiliated (F-P-) mutants. F+P+ and F-P+ bacteria efficiently adhered to mouse epidermal cells, while F+P- and F-P- bacteria hardly adhered to mouse epidermal cells. The number of F+P+ bacteria that adhered to mouse epidermal cells was almost the same as that of F-P+ bacteria. The number of F+P- bacteria that adhered to mouse epidermal cells was almost the same as that of F-P- bacteria. The adhesion of P+ (F+P+ and F-P+) bacteria was inhibited by antipilus serum, while that of P- (F+P- and F-P-) bacteria was not inhibited by antipilus serum. There were no significant differences between the number of bacteria adhering to mouse epidermal cells isolated from normal skin and those adhering to cells isolated from burned skin. Heating of the mouse epidermal cell suspension had no effect on the adhesion of P. aeruginosa. These results suggest that pili mediate the adhesion of P. aeruginosa to mouse epidermal cells and that P. aeruginosa adheres efficiently to mouse epidermal cells despite the loss of cell viability caused by burning. PMID:2886430

  11. Immune sensitization to methylene diphenyl diisocyanate (MDI) resulting from skin exposure: albumin as a carrier protein connecting skin exposure to subsequent respiratory responses

    PubMed Central

    2011-01-01

    Background Methylene diphenyl diisocyanate (MDI), a reactive chemical used for commercial polyurethane production, is a well-recognized cause of occupational asthma. The major focus of disease prevention efforts to date has been respiratory tract exposure; however, skin exposure may also be an important route for inducing immune sensitization, which may promote subsequent airway inflammatory responses. We developed a murine model to investigate pathogenic mechanisms by which MDI skin exposure might promote subsequent immune responses, including respiratory tract inflammation. Methods Mice exposed via the skin to varying doses (0.1-10% w/v) of MDI diluted in acetone/olive oil were subsequently evaluated for MDI immune sensitization. Serum levels of MDI-specific IgG and IgE were measured by enzyme-linked immunosorbant assay (ELISA), while respiratory tract inflammation, induced by intranasal delivery of MDI-mouse albumin conjugates, was evaluated based on bronchoalveolar lavage (BAL). Autologous serum IgG from "skin only" exposed mice was used to detect and guide the purification/identification of skin proteins antigenically modified by MDI exposure in vivo. Results Skin exposure to MDI resulted in specific antibody production and promoted subsequent respiratory tract inflammation in animals challenged intranasally with MDI-mouse albumin conjugates. The degree of (secondary) respiratory tract inflammation and eosinophilia depended upon the (primary) skin exposure dose, and was maximal in mice exposed to 1% MDI, but paradoxically limited in mice receiving 10-fold higher doses (e.g. 10% MDI). The major antigenically-modified protein at the local MDI skin exposure site was identified as albumin, and demonstrated biophysical changes consistent with MDI conjugation. Conclusions MDI skin exposure can induce MDI-specific immune sensitivity and promote subsequent respiratory tract inflammatory responses and thus, may play an important role in MDI asthma pathogenesis. MDI

  12. Spiritual and religious aspects of skin and skin disorders

    PubMed Central

    Shenefelt, Philip D; Shenefelt, Debrah A

    2014-01-01

    Skin and skin disorders have had spiritual aspects since ancient times. Skin, hair, and nails are visible to self and others, and touchable by self and others. The skin is a major sensory organ. Skin also expresses emotions detectable by others through pallor, coldness, “goose bumps”, redness, warmth, or sweating. Spiritual and religious significances of skin are revealed through how much of the skin has been and continues to be covered with what types of coverings, scalp and beard hair cutting, shaving and styling, skin, nail, and hair coloring and decorating, tattooing, and intentional scarring of skin. Persons with visible skin disorders have often been stigmatized or even treated as outcasts. Shamans and other spiritual and religious healers have brought about healing of skin disorders through spiritual means. Spiritual and religious interactions with various skin disorders such as psoriasis, leprosy, and vitiligo are discussed. Religious aspects of skin and skin diseases are evaluated for several major religions, with a special focus on Judaism, both conventional and kabbalistic. PMID:25120377

  13. [Autoimmune bullous skin disorders].

    PubMed

    Hertl, Michael; Niedermeier, Andrea; Borradori, Luca

    2010-09-01

    Autoimmune bullous skin disorders are rare, potentially fatal disorders of skin and mucous membranes which are associated with IgG or IgA autoantibodies against distinct adhesion molecules of the epidermis and dermal epidermal basement membrane zone, respectively. These autoantibodies lead to a loss of skin adhesion which shows up clinically as the formation of blisters or erosions. In pemphigus, loss of adhesion occurs within the epidermis while in the pemphigoids, linear IgA dermatosis, epidermolysis bullosa acquisita and dermatitis herpetiformis, loss of adhesion takes place within or underneath the basement membrane zone. The autoantigens of these disorders are largely identified and characterized. Making the diagnosis of autoimmune bullous skin diseases is based on histology and direct immunofluorescence of perilesional skin and the serological detection of autoantibodides by indirect immunofluorescence and recombinant autoantigens. Therapeutically, systemic treatment with glucocorticoids is combined with immunosuppressive adjuvants which allow for the fast reduction of systemic steroids. A prospective trial in pemphigus showed that adjuvant treatment with azathioprine, mycophenolate mofetil and cyclophosphamide, respectively, led to a significant reduction of the cummulative dose of systemic steroids until complete clinical remission was achieved. In bullous pemphigoid, topical treatment with clobetasol led to complete clinical remissions without major side effects seen when glucocorticoids were applied systemically. Therapeutic depletion of B cells by rituximab as a second line therapy has significantly improved the overall prognosis of pemphigus. Comparable controlled therapeutic trials have not yet been performed in dermatitis herpetiformis and epidermolysis bullosa acquisita.

  14. Increased in vivo skin penetration of quantum dots with UVR and in vitro quantum dot cytotoxicity

    NASA Astrophysics Data System (ADS)

    Mortensen, Luke; Zheng, Hong; Faulknor, Renea; De Benedetto, Anna; Beck, Lisa; DeLouise, Lisa A.

    2009-02-01

    The growing presence of quantum dots (QD) in a variety of biological, medical, and electronics applications means an increased risk of human exposure in manufacturing, research, and consumer use. However, very few studies have investigated the susceptibility of skin to penetration of QD - the most common exposure route- and the results of those that exist are conflicting. This suggests that a technique allowing determination of skin barrier status and prediction of skin permeability to QD would be of crucial interest as recent findings have provided evidence of in vitro cytotoxicity and long-term in vivo retention in the body for most QD surface chemistries. Our research focuses on barrier status of the skin (intact and with ultraviolet radiation induced barrier defect) and its impact on QD skin penetration. These model studies are particularly relevant to the common application condition of NP containing sunscreen and SPF cosmetics to UV exposed skin. Herein we present our initial efforts to develop an in vivo model of nanoparticle skin penetration using the SKH-1 hairless mouse with transepidermal water loss (TEWL) to evaluate skin barrier status and determine its ability to predict QD penetration. Our results show that ultraviolet radiation increases both TEWL and skin penetration of QD. Additionally, we demonstrate cytotoxic potential of QD to skin cells using a metastatic melanoma cell line. Our research suggests future work in specific targeting of nanoparticles, to prevent or enhance penetration. This knowledge will be used to develop powerful therapeutic agents, decreased penetration cosmetic nanoparticles, and precise skin cancer imaging modalities.

  15. Non-invasive measurement of melanin-derived radicals in living mouse tail using X-band EPR

    PubMed Central

    Ogawa, Yukihiro; Ueno, Megumi; Sekine-Suzuki, Emiko; Nakanishi, Ikuo; Matsumoto, Ken-ichiro; Fujisaki, Shingo

    2016-01-01

    The aim of this experiment is to measure in vivo generation of melanin-derived radicals non-invasively, as a quantifiable index of radio-biological effect. Melanin-derived radicals in a living intact mouse tail tip were non-invasively measured in very simple way using an X-band electron paramagnetic resonance spectrometer. Colored mouse strains, C57BL/6NCr, BDF1, and C3H/He, have clear EPR signal corresponding to melanin-derived radicals in the tail tip; however, albino mouse strains, BALB/cCr, ddY, ICR, have no EPR signals. An X-ray fraction of 2 Gy/day (1 Gy/min) was repeatedly irradiated to a C3H/He mouse tail skin every Monday to Friday for 4 weeks. In comparison to before starting irradiation, the C3H/He mouse tail skin became darker, like a suntan. The melanin-derived radicals in C3H/He mouse tail skin were increased in association with X-ray fractions. Melanin-derived radicals in mouse tail skin can be readily and chronologically measurable by using X-band EPR spectrometer, and can be a marker for a radiobiological effect in the skin. PMID:27895382

  16. Skin friction balance

    NASA Technical Reports Server (NTRS)

    Ping, Tcheng (Inventor); Supplee, Frank H., Jr. (Inventor)

    1989-01-01

    A skin friction balance uses a parallel linkage mechanism to avoid inaccuracies in skin friction measurement attributable to off-center normal forces. The parallel linkage mechanism includes a stationary plate mounted in a cage, and an upper and lower movable plate which are linked to each other and to the stationary plate throught three vertical links. Flexure pivots are provided for pivotally connecting the links and the plates. A sensing element connected to the upper plate moves in response to skin friction, and the lower plate moves in the opposite direction of the upper plate. A force motor maintains a null position of the sensing element by exerting a restoring force in response to a signal generated by a linear variable differential transformer (LVDT).

  17. Update on skin allergy.

    PubMed

    Schlapbach, C; Simon, D

    2014-12-01

    Skin diseases with an allergic background such as atopic dermatitis, allergic contact dermatitis, and urticaria are very common. Moreover, diseases arising from a dysfunction of immune cells and/or their products often manifest with skin symptoms. This review aims to summarize recently published articles in order to highlight novel research findings, clinical trial results, and current guidelines on disease management. In recent years, an immense progress has been made in understanding the link between skin barrier dysfunction and allergic sensitization initiating the atopic march. In consequence, new strategies for treatment and prevention have been developed. Novel pathogenic insights, for example, into urticaria, angioedema, mastocytosis, led to the development of new therapeutic approaches and their implementation in daily patient care. By understanding distinct pathomechanisms, for example, the role of IL-1, novel entities such as autoinflammatory diseases have been described. Considerable effort has been made to improve and harmonize patient management as documented in several guidelines and position papers.

  18. Sprayed skin turbine component

    DOEpatents

    Allen, David B

    2013-06-04

    Fabricating a turbine component (50) by casting a core structure (30), forming an array of pits (24) in an outer surface (32) of the core structure, depositing a transient liquid phase (TLP) material (40) on the outer surface of the core structure, the TLP containing a melting-point depressant, depositing a skin (42) on the outer surface of the core structure over the TLP material, and heating the assembly, thus forming both a diffusion bond and a mechanical interlock between the skin and the core structure. The heating diffuses the melting-point depressant away from the interface. Subsurface cooling channels (35) may be formed by forming grooves (34) in the outer surface of the core structure, filling the grooves with a fugitive filler (36), depositing and bonding the skin (42), then removing the fugitive material.

  19. Environment and the skin

    SciTech Connect

    Suskind, R.R. )

    1990-03-01

    The skin is an important organ of defense adaptation and a portal of entry for xenobiotics. It is vulnerable to physical, chemical, and biologic agents and capable of expressing responses to these agents in a variety of pathologic patterns. These patterns are characterized by morphologic and functional features which are elicited by careful examination and test procedures. Cutaneous cancer may result from exposure to nonionizing as well as ionizing radiation, to specific identifiable chemical hazards, and may be enhanced by trauma. Cutaneous hazards of chemical sources are largely found in the workplace and among consumer products, including drugs and toilet goods. Environmental skin diseases and injuries are preventable. Prior to use assessment for safety and for possible risks from exposure to an agent, product, or process is of primary importance in the prevention and control of environmental skin disease and injury.

  20. In vivo stepwise multi-photon activation fluorescence imaging of melanin in human skin

    NASA Astrophysics Data System (ADS)

    Lai, Zhenhua; Gu, Zetong; Abbas, Saleh; Lowe, Jared; Sierra, Heidy; Rajadhyaksha, Milind; DiMarzio, Charles

    2014-03-01

    The stepwise multi-photon activated fluorescence (SMPAF) of melanin is a low cost and reliable method of detecting melanin because the activation and excitation can be a continuous-wave (CW) mode near infrared (NIR) laser. Our previous work has demonstrated the melanin SMPAF images in sepia melanin, mouse hair, and mouse skin. In this study, we show the feasibility of using SMPAF to detect melanin in vivo. in vivo melanin SMPAF images of normal skin and benign nevus are demonstrated. SMPAF images add specificity for melanin detection than MPFM images and CRM images. Melanin SMPAF is a promising technology to enable early detection of melanoma for dermatologists.