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.

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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)).

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.

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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.

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

International Nuclear Information System (INIS)

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

2013-01-01

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

Fibre optic confocal imaging (FOCI) of keratinocytes, blood vessels and nerves in hairless mouse skin in vivo

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BUSSAU, L. J.; VO, L. T.; DELANEY, P. M.; PAPWORTH, G. D.; BARKLA, D. H.; KING, R. G.

1998-01-01

Fibre optic confocal imaging (FOCI) enabled subsurface fluorescence microscopy of the skin of hairless mice in vivo. Application of acridine orange enabled imaging of the layers of the epidermis. The corneocytes of the stratum corneum, the keratinocytes in the basal layers and redundant hair follicles were visualised at depths greater than 100 μm. Cellular and nuclear membranes of keratinocytes of the skin were visualised by the use of acridine orange and DIOC5(3). Imaging of the skin after injection of FITC-dextran revealed an extensive network of blood vessels with a size range up to 20 μm. Blood cells could be seen moving through dermal vessels and the blood circulation through the dermal vascular bed was video-taped. The fluorescent dye 4-di-2-ASP showed the presence of nerves fibres around the hair follicles and subsurface blood vessels. Comparison was made between images obtained in vivo using FOCI and in vitro scanning electron microscopy and conventional histology. FOCI offers the potential to study dynamic events in vivo, such as blood flow, skin growth, nerve regeneration and many pathological processes, in ways which have not previously been possible. PMID:9643419

Protective effect of mango (Mangifera indica L.) against UVB-induced skin aging in hairless mice.

Science.gov (United States)

Song, Jae Hyoung; Bae, Eun Young; Choi, Goya; Hyun, Jin Won; Lee, Mi Young; Lee, Hye Won; Chae, Sungwook

2013-04-01

Mangifera indica L. (Anacardiaceae) is a medicinal plant whose extracts have been described as an antioxidant with anti-inflammatory and immunomodulatory activities. Skin aging is a consequence of chronic sun exposure to the sun and therefore ultraviolet (UV) radiation. Naturally occurring antioxidants are known to reduce skin aging. Therefore, the aim of the present study was to evaluate the protective role of mango extract against UVB-induced skin aging in hairless mice. HR-1 hairless male mice (6 weeks old) were divided into three groups: control (n = 5), UVB-treated vehicle (n = 5), and UVB-treated mango extract (n = 5) groups. UVB-irradiated mice from the mango extract group were orally administered 0.1 ml of water containing 100 mg of mango extract/kg body weight per day. The inhibitory activity of mango extract on wrinkle formation was determined by the analysis of the skin replica, epidermal thickness based on histological examination, and damage to collagen fiber. The mean length of wrinkles in UVB-treated vehicle group significantly improved after the oral administration of mango extract, which significantly inhibited the increase in epidermal thickness and epidermal hypertrophy (P mango extract by Masson's trichrome staining. These results indicate that mango extract showed anti-photoaging activity in UVB-irradiated hairless mice. © 2013 John Wiley & Sons A/S.

Time course of skin features and inflammatory biomarkers after liquid sulfur mustard exposure in SKH-1 hairless mice.

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Mouret, Stéphane; Wartelle, Julien; Batal, Mohamed; Emorine, Sandy; Bertoni, Marine; Poyot, Thomas; Cléry-Barraud, Cécile; Bakdouri, Nacera El; Peinnequin, André; Douki, Thierry; Boudry, Isabelle

2015-01-05

Sulfur mustard (SM) is a strong bifunctional alkylating agent that produces severe tissue injuries characterized by erythema, edema, subepidermal blisters and a delayed inflammatory response after cutaneous exposure. However, despite its long history, SM remains a threat because of the lack of effective medical countermeasures as the molecular mechanisms of these events remain unclear. This limited number of therapeutic options results in part of an absence of appropriate animal models. We propose here to use SKH-1 hairless mouse as the appropriate model for the design of therapeutic strategies against SM-induced skin toxicity. In the present study particular emphasis was placed on histopathological changes associated with inflammatory responses after topical exposure of dorsal skin to three different doses of SM (0.6, 6 and 60mg/kg) corresponding to a superficial, a second-degree and a third-degree burn. Firstly, clinical evaluation of SM-induced skin lesions using non invasive bioengineering methods showed that erythema and impairment of skin barrier increased in a dose-dependent manner. Histological evaluation of skin sections exposed to SM revealed that the time to onset and the severity of symptoms including disorganization of epidermal basal cells, number of pyknotic nuclei, activation of mast cells and neutrophils dermal invasion were dose-dependent. These histopathological changes were associated with a dose- and time-dependent increase in expression of specific mRNA for inflammatory mediators such as interleukins (IL1β and IL6), tumor necrosis factor (TNF)-α, cycloxygenase-2 (COX-2), macrophage inflammatory proteins (MIP-1α, MIP-2 and MIP-1αR) and keratinocyte chemoattractant (KC also called CXCL1) as well as adhesion molecules (L-selectin and vascular cell adhesion molecule (VCAM)) and growth factor (granulocyte colony-stimulating factor (Csf3)). A dose-dependent increase was also noted after SM exposure for mRNA of matrix metalloproteinases (MMP9

Oral Administration of Fermented Soymilk Products Protects the Skin of Hairless Mice against Ultraviolet Damage

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Mitsuyoshi Kano

2016-08-01

Full Text Available The protective effect of isoflavones on skin damage from ultraviolet (UV radiation and their bioavailability were investigated in ovariectomized hairless mice fed diets composed of fermented soymilk containing aglycone forms of isoflavones or control soymilk containing glucose-conjugated forms of isoflavones. The erythema intensity of dorsal skin was significantly higher in ovariectomized mice than in sham-operated mice (p < 0.05. The erythema intensity and epidermal thickness of dorsal skin were significantly lower in the fermented soymilk diet group than in the control diet group (each p < 0.05. Levels of cyclobutane pyrimidine dimers in dorsal skin were significantly lower in the fermented soymilk diet group than in the control group (p < 0.05. Serum and dorsal skin isoflavone concentrations were significantly higher in the fermented soymilk diet group than in the soymilk diet group (p < 0.05. These results indicate that oral administration of a fermented soymilk diet increases isoflavone concentrations in the blood and skin, effectively scavenging the reactive oxygen species generated by UV irradiation and exerting an estrogen-like activity, with a consequent protective effect on skin photodamage in hairless mice.

Protection against photoaging in the hairless mouse by the isoflavone equol.

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Reeve, Vivienne E; Widyarini, Sitarina; Domanski, Diane; Chew, Elaine; Barnes, Karen

2005-01-01

Topical application of the isoflavone equol immediately following solar-simulated UV (SSUV) radiation exposure has previously been demonstrated to have significant photoprotective effects. Equol reduced both the inflammatory edema and the systemic suppression of the contact hypersensitivity reaction in hairless mice. Furthermore, daily topical equol application immediately following irradiation during a 10-week chronic SSUV exposure regime also reduced photocarcinogenesis severity in the mouse. This study examines the potential for topical equol to prevent photoaging in response to chronic SSUV irradiation for up to 30 weeks. We did not find consistent expression of the characteristic markers of photoaging until 30 weeks, although moderate epidermal hyperplasia and a transient increase in dermal mast cell numbers were evident after 1 week. Daily application of 10 muM equol lotion significantly reduced these early changes. However after 30 weeks of SSUV exposure, photoaging was well developed, as shown histologically by markedly increased epidermal hyperplasia, increased dermal mast cell number, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis. Topical equol treatment protected significantly from each of these impairments, as demonstrated histologically and quantitatively. Additionally, equol was found to have strong antioxidant action against acute UVA (320-400 nm)-induced lipid peroxidation of mouse skin, this property accounting for its antiphotoaging mechanism. The evidence for equol's antiphotoaging activity, taken together with its anti-inflammatory, immunoprotective and anticarcinogenic efficacy against SSUV irradiation in the mouse, suggests that equol could be developed as a helpful topical photoprotective agent for daily use by humans.

Antioxidant and Anti-Inflammatory Effects of Shungite against Ultraviolet B Irradiation-Induced Skin Damage in Hairless Mice

Directory of Open Access Journals (Sweden)

Ma. Easter Joy Sajo

2017-01-01

Full Text Available As fullerene-based compound applications have been rapidly increasing in the health industry, the need of biomedical research is urgently in demand. While shungite is regarded as a natural source of fullerene, it remains poorly documented. Here, we explored the in vivo effects of shungite against ultraviolet B- (UVB- induced skin damage by investigating the physiological skin parameters, immune-redox profiling, and oxidative stress molecular signaling. Toward this, mice were UVB-irradiated with 0.75 mW/cm2 for two consecutive days. Consecutively, shungite was topically applied on the dorsal side of the mice for 7 days. First, we found significant improvements in the skin parameters of the shungite-treated groups revealed by the reduction in roughness, pigmentation, and wrinkle measurement. Second, the immunokine profiling in mouse serum and skin lysates showed a reduction in the proinflammatory response in the shungite-treated groups. Accordingly, the redox profile of shungite-treated groups showed counterbalance of ROS/RNS and superoxide levels in serum and skin lysates. Last, we have confirmed the involvement of Nrf2- and MAPK-mediated oxidative stress pathways in the antioxidant mechanism of shungite. Collectively, the results clearly show that shungite has an antioxidant and anti-inflammatory action against UVB-induced skin damage in hairless mice.

In vivo quantification of quantum dot systemic transport in C57BL/6 hairless mice following skin application post-ultraviolet radiation.

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Jatana, Samreen; Palmer, Brian C; Phelan, Sarah J; Gelein, Robert; DeLouise, Lisa A

2017-04-14

Previous work has demonstrated size, surface charge and skin barrier dependent penetration of nanoparticles into the viable layers of mouse skin. The goal of this work was to characterize the tissue distribution and mechanism of transport of nanoparticles beyond skin, with and without Ultraviolet Radiation (UVR) induced skin barrier disruption. Atomic absorption spectroscopy (AAS), flow cytometry and confocal microscopy were used to examine the effect of UVR dose (180 and 360 mJ/cm 2 UVB) on the skin penetration and systemic distribution of quantum dot (QD) nanoparticles topically applied at different time-points post UVR using a hairless C57BL/6 mouse model. Results indicate that QDs can penetrate mouse skin, regardless of UVR exposure, as evidenced by the increased cadmium in the local lymph nodes of all QD treated mice. The average % recovery for all treatment groups was 69.68% with ~66.84% of the applied dose recovered from the skin (both epicutaneous and intracutaneous). An average of 0.024% of the applied dose was recovered from the lymph nodes across various treatment groups. When QDs are applied 4 days post UV irradiation, at the peak of the skin barrier defect and LC migration to the local lymph node, there is an increased cellular presence of QD in the lymph node; however, AAS analysis of local lymph nodes display no difference in cadmium levels due to UVR treatment. Our data suggests that Langerhans cells (LCs) can engulf QDs in skin, but transport to the lymph node may occur by both cellular (dendritic and macrophage) and non-cellular mechanisms. It is interesting that these specific nanoparticles were retained in skin similarly regardless of UVR barrier disruption, but the observed skin immune cell interaction with nanoparticles suggest a potential for immunomodulation, which we are currently examining in a murine model of skin allergy.

Histogenesis and progression of ultraviolet light-induced tumors in hairless mice

International Nuclear Information System (INIS)

Kligman, L.H.; Kligman, A.M.

1981-01-01

Tumor histogenesis and progression were studied in UV-irradiated albino (Skh:hairless-1) and lightly pigmented (Skh:hairless-2) hairless mice. A strongly carcinogenic dose of UV light was used, producing 100% tumor incidence by 35 weeks. The light source emitted mainly UV radiation in the range of 280-320 nm and the less energetic UV radiation up to 400 nm. The resulting epidermal changes and neoplasms resembled those seen in the actinically damaged skin of humans. Microscopic lesions included benign hyperplasia, actinic keratoses, and squamous cell carcinoma in situ and with microinvasion. Clinical tumors were epithelial papillomas, fibropapillomas, keratoacanthomas, cystic keratomas, benign pigmented macules, cutaneous hornlike growths, exophytic and endophytic squamous cell carcinomas of several cytologic types, and fibrosarcomas. Even with this high dose of UV radiation, not all of the small tumors progressed to cancer. Many regressed, including some keratoacanthomas, whereas others remained small and benign for the lifetime of the mouse

Photoprotective effect of vitamins A and E on polyamine and oxygenated free radical metabolism in hairless mouse epidermis.

Science.gov (United States)

Khettab, N; Amory, M C; Briand, G; Bousquet, B; Combre, A; Forlot, P; Barey, M

1988-12-01

The purpose of this study was to confirm the photoprotective effect on skin of vitamins A and E, due to inhibition of polyamine synthesis and production of free radicals. These variables were measured in the lumbar epidermis of the female hairless mouse subjected to UVA + B irradiation. Polyamines were assayed in epidermal homogenate by HPLC, and production of oxygenated free radicals was determined by spectrofluorometric assay of malonyl dialdehyde. It was determined that butyl-hydroxy-toluene and vitamin E inhibited production of free radicals (56% and 60%, respectively) and caused a significant reduction in polyamine biosynthesis (P less than 0.01), whereas the inhibitory effect of malonyl dialdehyde induced by vitamin A (30%) had no associated effect on polyamine metabolism.

Injury Thresholds for Topical Cream-Coated Skin of Hairless Guinea Pigs (Cavia Procellus) in Near Infrared Region

National Research Council Canada - National Science Library

Stolarski, David J; Zohner, Justin J; Imholte, Michelle L; Chavey, Lucas J; Pocock, Ginger M; Buchanan, Kelvin C; Jindra, Nichole M; Figueroa, Manuel A; Thomas, Robert J; Rockwell, Benjamin A

2006-01-01

.... Hairless guinea pigs (cavia porcellus) in vivo were used to evaluate how the minimum visible lesion threshold for single-pulse laser exposure is changed with a topical agent applied to the skin...

Photoprotective effects of two natural products on ultraviolet B-induced oxidative stress and apoptosis in SKH-1 mouse skin.

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Filip, Adriana; Daicoviciu, Doina; Clichici, Simona; Mocan, Teodora; Muresan, Adriana; Postescu, Ion Dan

2011-01-01

Solar ultraviolet radiation (UV) is the major cause of nonmelanoma skin cancer in humans. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. We studied the photoprotective activity of Calluna vulgaris and red grape seed (Vitis vinifera L, Burgund Mare variety [BM]) extracts in vivo in an SKH-1 hairless mice skin model. Fifty 8-week-old female SKH-1 hairless mice were randomly divided into 5 groups (n = 10 each): controls, UVB-irradiated, C. vulgaris plus UVB-irradiated, BM plus UVB-irradiated, and epigallocatechin gallate (EGCG) plus UVB-irradiated. A dose of 4 mg/mouse per cm² of skin area for both extracts was topically applied to the mice 30 minutes before a single-dose (240 mJ/cm²) UVB exposure. EGCG dissolved in phosphate-buffered saline (pH 6.6; 0.067 M) was administered at 2 mg/mouse per cm². Glutathione peroxidase and catalase activities, reduced glutathione (GSH), malondialdehyde, nitric oxide, and caspase 3 activity were determined in skin homogenates 24 hours after irradiation. A single dose of UVB increased GSH levels and glutathione peroxidase activity in the exposed skin. C. vulgaris and BM pretreatment significantly decreased GSH formation and glutathione peroxidase activity (P treatments with C. vulgaris and particularly BM extracts (P < .002) significantly reduced caspase 3 activity, indicating that the cells were protected against apoptosis. These results suggest that C. vulgaris and BM extracts might be chemopreventive candidates for reducing UV-induced risk for skin cancer.

Oral administration of Bifidobacterium breve attenuates UV-induced barrier perturbation and oxidative stress in hairless mice skin.

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Ishii, Yuki; Sugimoto, Saho; Izawa, Naoki; Sone, Toshiro; Chiba, Katsuyoshi; Miyazaki, Kouji

2014-07-01

Recent studies have shown that some probiotics affect not only the gut but also the skin. However, the effects of probiotics on ultraviolet (UV)-induced skin damage are poorly understood. In this study, we aim to examine whether oral administration of live Bifidobacterium breve strain Yakult (BBY), a typical probiotic, can attenuate skin barrier perturbation caused by UV and reactive oxygen species (ROS) in hairless mice. The mice were orally supplemented with a vehicle only or BBY once a day for nine successive days. Mouse dorsal skin was irradiated with UV from days 6 to 9. The day after the final irradiation, the transepidermal water loss (TEWL), stratum corneum hydration, and oxidation-related factors of the skin were evaluated. We elucidated that BBY prevented the UV-induced increase in TEWL and decrease in stratum corneum hydration. In addition, BBY significantly suppressed the UV-induced increase in hydrogen peroxide levels, oxidation of proteins and lipids, and xanthine oxidase activity in the skin. Conversely, antioxidant capacity did not change regardless of whether BBY was administered or not. In parameters we evaluated, there was a positive correlation between the increase in TEWL and the oxidation levels of proteins and lipids. Our results suggest that oral administration of BBY attenuates UV-induced barrier perturbation and oxidative stress of the skin, and this antioxidative effect is not attributed to enhancement of antioxidant capacity but to the prevention of ROS generation.

Selenium inhibits UV-light-induced skin carcinogenesis in hairless mice

International Nuclear Information System (INIS)

Overvad, Kim; Thorling, E.B.; Bjerring, Peter; Ebbesen, Peter

1985-01-01

Female hairless inbred hr/hr mice were exposed to UV-B irradiation from Philips TL 40W/13 fluorescent tubes. Fractionated irradiation, given as single daily doses 5 days a week, was gradually increased from 0.04 to 0.4 J/cm 2 over 2 weeks. Irradiation at 0.4 J/cm 2 was continued for 20 weeks. Selenium supplementation given as sodium selenite in the drinking water at 2, 4 and 8 mg/l began 3 weeks before UV-irradiation and continued thereafter. Development of skin tumors was followed by weekly examinations. Statistical analyses revealed significant dose-dependent selenium-mediated protection against UV-light-induced skin cancer. Leukemia developed in 5 of 150 UV-irradiated mice as opposed to none in a group of 60 unirradiated mice. (author)

Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs

OpenAIRE

Banks, Stan L.; Pinninti, Raghotham R.; Gill, Harvinder S.; Paudel, Kalpana S.; Crooks, Peter A.; Brogden, Nicole K.; Prausnitz, Mark R.; Stinchcomb, Audra L.

2010-01-01

Controlled-release delivery of 6-β-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. Micro...

Connective tissue photodamage in the hairless mouse is partially reversible

International Nuclear Information System (INIS)

Kligman, L.H.

1987-01-01

Photodamaged connective tissue in animal and human skin is characterized by excessive accumulations of elastic fibers, loss of mature collagen, concomitant overproduction of new collagen, and greatly increased levels of glycosaminoglycans. Formerly considered irreversible changes, we recently showed in hairless mice, post irradiation, that a band of normal connective tissue was laid down subepidermally. The present studies focused on 2 aspects of this repair: whether repair would occur if animals were protected by sunscreens after dermal damage was induced and irradiation continued; whether retinoic acid could enhance the repair process. To examine the first aspect, albino hairless mice were irradiated with Westinghouse FS 20 sunlamps thrice weekly for 30 weeks. Sunscreens of high sun-protection factors were applied after 10 and 20 weeks. Not only was further damage prevented, but the damage incurred before sunscreen application was repaired. This appeared as subepidermal reconstruction zones containing normal, mature collagen and a network of fine elastic fibers. The second aspect was examined by applying 0.05% retinoic acid, topically, to animals preirradiated for 10 weeks. In contrast to controls treated with vehicle, the reconstruction zone was significantly wider in retinoic acid-treated mice. The enhanced repair was dose-related

The response of mouse skin to re-irradiation with x-rays or fast neutrons

International Nuclear Information System (INIS)

Tsukiyama, Iwao; Egawa, Sunao; Kumazawa, Akiyoshi; Iino, Yuu.

1986-01-01

Effects of neutrons and x-rays on mouse skin which had been previously irradiated with x-rays were investigated. Two tattoo marks were placed in the hairless legs of mice at intervals of 15 mm. The legs were exposed to various doses of x-ray and neutrons to determine the relative biological effectiveness (RBE) using the contraction of the skin as an index. The RBE was 0.93 - 1.73. The legs of the mice were preexposed to 25 Gy of x-ray, and exposed 4 months later. The contraction of the skin began earlier than after the first irradiation. RBE was 2.18 - 2.47. This RBE was higher than that in untreated mice. These results suggest that previously irradiated normal tissues are much more sensitive to neutrons than to x-rays. (author)

Chyawanprash, a formulation of traditional Ayurvedic medicine, shows a protective effect on skin photoaging in hairless mice.

Science.gov (United States)

Takauji, Yuki; Morino, Kyoko; Miki, Kensuke; Hossain, Mohammad; Ayusawa, Dai; Fujii, Michihiko

2016-11-01

Chronic exposure to ultraviolet (UV) radiation induces skin photoaging (premature skin aging). UV irradiation generates reactive oxygen species (ROS), which are shown to play a pivotal role in skin photoaging. Ayurveda is a holistic traditional medical system, and Chyawanprash is one of the most popular formulations in Ayurveda. Since maintenance of the function and appearance of skin is important, we examined whether Chyawanprash has a protective effect on skin photoaging. To examine the effect of Chyawanprash on skin photoaging, hairless mice were administered with Chyawanprash in drinking water for 3 weeks, and then repeatedly exposed to ultraviolet light B (UVB) irradiation (225 or 450 mJ/cm 2 ) to induce skin photoaging. To further examine the function of Chyawanprash, its effects were examined in cells cultured in vitro. Chyawanprash was added in culture medium, and examined for the effect on the growth of human keratinocytes, and for the ability to eliminate ROS which generated by paraquat (50 μmol/L) in HeLa cells. UVB irradiation caused symptoms such as rough skin, erythema, and edema on the skin in hairless mice, but administration of Chyawanprash relieved these symptoms. Further, Chyawanprash significantly suppressed epidermal thickening, a typical marker of skin photoaging, in mice. We then analyzed the effect of Chyawanprash in human cells in culture, and found that Chyawanprash enhanced the growth of human keratinocytes, and efficiently eliminated ROS, which are causally involved in skin photoaging, in HeLa cells. These findings suggested that Chyawanprash may have beneficial effects on slowing skin photoaging.

Tritium activity balance in hairless rats following skin-contact exposure to tritium-gas-contaminated stainless-steel surfaces

Energy Technology Data Exchange (ETDEWEB)

Trivedi, A

1994-06-01

Studies using animals and human volunteers have demonstrated that the dosimetry for skin-contact exposure to contaminated metal surfaces differs from that for the intake of tritiated water or tritium gas. However, despite the availability of some information on the dosimetry for skin-contact with tritium-gas-contaminated metal surfaces, uncertainties in estimating skin doses remain, because of poor accounting for the applied tritium activity in the body (Eakins et al., 1975; Trivedi, 1993). Experiments on hairless rats were performed to account for the tritium activity applied onto the skin. Hairless rats were contaminated through skin-contact exposure to tritium-gas-contaminated stainless-steel planchets. The activity in the first smear was about 35% of the total removable activity (measured by summing ten consecutive swipes). The amount of tritium applied onto the skin can be approximated by estimating the tritium activity in the first smear removed form the contaminated surfaces. 87 {+-} 9% of the transferred tritium was retained in the exposed skin 30 min post-exposure. 30 min post exposure, the unexposed skin and the carcass retained 8 {+-} 6% and 3 {+-} 2% of the total applied tritium activity, respectively. The percentage of tritium evolved from the body or breathed out was estimated to be 2 {+-} 1% of the total applied activity 30 min post-exposure. It is recommended that to evaluate accurately the amount of tritium transferred to the skin, alternative measurement approaches are required that can directly account for the transferred activity onto the skin. 15 refs., 13 tabs., 7 figs.

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

International Nuclear Information System (INIS)

Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja; Joseph, Binoy; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Yin, Yuanqin; Roy, Ram Vinod; Lu, Jian; Zhang, Zhuo; Wang, Yitao

2014-01-01

Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE 2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE 2 production. • C3G inhibited

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin

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Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin; Divya, Sasidharan Padmaja [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Joseph, Binoy [Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky, Lexington, KY 40536-0509 (United States); Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Yin, Yuanqin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Cancer Institute, The First Affiliated Hospital, China Medical University, Shenyang (China); Roy, Ram Vinod [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Lu, Jian [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); and others

2014-10-01

Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE{sub 2} and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2′-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. - Highlights: • C3G inhibited UVB-induced oxidative damage and inflammation. • C3G inhibited UVB-induced COX-2, iNOS and PGE{sub 2} production. • C3G

Comparison of the acute ultraviolet photoresponse in congenic albino hairless C57BL/6J mice relative to outbred SKH1 hairless mice

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Konger, Raymond L.; Derr-Yellin, Ethel; Hojati, Delaram; Lutz, Cathleen; Sundberg, John P.

2016-01-01

Hairless albino Crl:SKH1-Hrhr mice are commonly utilized for studies in which hair or pigmentation would introduce an impediment to observational studies. Being an outbred strain, the SKH1 model suffers from key limitations that are not seen with congenic mouse strains. Inbred and congenic C57BL/6J mice are commonly utilized for modified genetic mouse models. We compare the acute UV-induced photoresponse between outbred SKH1 mice and an immune competent, hairless, albino C57BL/6J congenic mouse line [B6.Cg-Tyrc-2J Hrhr/J]. Histologically, B6.Cg-Tyrc-2J Hrhr/J skin is indistinguishable from that of SKH1 mice. The skin of both SKH1 and B6.Cg-Tyrc-2J Hrhr/J mice exhibited a reduction in hypodermal adipose tissue, the presence of utricles and dermal cystic structures, the presence of dermal granulomas, and epidermal thickening. In response to a single 1500 J/m2 UVB dose, the edema and apoptotic response was equivalent in both mouse strains. However, B6.Cg-Tyrc-2J Hrhr/J mice exhibited a more robust delayed sunburn reaction, with an increase in epidermal erosion, scab formation, and myeloperoxidase activity relative to SKH1 mice. Compared with SKH1 mice, B6.Cg-Tyrc-2J Hrhr/J also exhibited an aberrant proliferative response to this single UV exposure. Epidermal Ki67 immunopositivity was significantly suppressed in B6.Cg-Tyrc-2J Hrhr/J mice at 24 hours post-UV. A smaller non-significant reduction in Ki67 labeling was observed in SKH1 mice. Finally, at 72 hours post-UV, SKH1 mice, but not B6.Cg-Tyrc-2J Hrhr/J mice, exhibited a significant increase in Ki67 immunolabeling relative to non-irradiated controls. Thus, B6.Cg-Tyrc-2J Hrhr/J mice are suitable for photobiology experiments. PMID:27095432

Oral administration of Aloe vera gel powder prevents UVB-induced decrease in skin elasticity via suppression of overexpression of MMPs in hairless mice.

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Saito, Marie; Tanaka, Miyuki; Misawa, Eriko; Yao, Ruiquing; Nabeshima, Kazumi; Yamauchi, Kouji; Abe, Fumiaki; Yamamoto, Yuki; Furukawa, Fukumi

2016-07-01

This study reports the effects of oral Aloe vera gel powder (AVGP) containing Aloe sterols on skin elasticity and the extracellular matrix in ultraviolet B (UVB)-irradiated hairless mice. Ten-week-old hairless mice were fed diets containing 0.3% AVGP for 8 weeks and irradiated UVB for 6 weeks. Mice treated with AVGP showed significant prevention of the UVB-induced decrease in skin elasticity. To investigate the mechanism underlying this suppression of skin elasticity loss, we measured the expression of matrix metalloproteinase (MMP)-2, -9, and -13. AVGP prevented both the UVB-induced increases in MMPs expressions. Moreover, we investigated hyaluronic acid (HA) content of mice dorsal skin and gene expression of HA synthase-2 (Has2). In the results, AVGP oral administration prevented UVB-induced decreasing in skin HA content and Has2 expression and attenuates the UVB-induced decrease in serum adiponectin, which promotes Has2 expression. These results suggested that AVGP has the ability to prevent the skin photoaging.

Hairless pigmented guinea pigs: a new model for the study of mammalian pigmentation.

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Bolognia, J L; Murray, M S; Pawelek, J M

1990-09-01

A stock of hairless pigmented guinea pigs was developed to facilitate studies of mammalian pigmentation. This stock combines the convenience of a hairless animal with a pigmentary system that is similar to human skin. In both human and guinea pig skin, active melanocytes are located in the basal layer of the interfollicular epidermis. Hairless albino guinea pigs on an outbred Hartley background (CrI:IAF/HA(hr/hr)BR; designated hr/hr) were mated with red-haired guinea pigs (designated Hr/Hr). Red-haired heterozygotes from the F1 generation (Hr/hr) were then mated with each other or with hairless albino guinea pigs. The F2 generation included hairless pigmented guinea pigs that retained their interfollicular epidermal melanocytes and whose skin was red-brown in color. Following UV irradiation, there was an increase in cutaneous pigmentation as well as an increase in the number of active epidermal melanocytes. An additional strain of black hairless guinea pigs was developed using black Hr/Hr animals and a similar breeding scheme. These two strains should serve as useful models for studies of the mammalian pigment system.

Circadian rhythms on skin function of hairless rats: light and thermic influences.

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Flo, Ana; Díez-Noguera, Antoni; Calpena, Ana C; Cambras, Trinitat

2014-03-01

Circadian rhythms are present in most functions of living beings. We have demonstrated the presence of circadian rhythms in skin variables (transepidermal water loss, TEWL; stratum corneum hydration, SCH; and skin temperature) in hairless rats under different environmental conditions of light and temperature. Circadian rhythms in TEWL and SCH showed mean amplitudes of about 20% and 14% around the mean, respectively, and appeared under light-dark cycles as well as under constant darkness. Environmental temperature was able to override TEWL, but not SCH rhythm, evidencing the dependency of TEWL on the temperature. Mean daily values of TEWL and SCH, and also the amplitude of TEWL rhythm, increased with the age of the animal. Under constant light, situation that induces arrhythmicity in rats, SCH and TEWL were inversely correlated. The results suggest the importance to take into account the functional skin rhythms in research in dermatological sciences. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hypochlorite Solution as a Decontaminant in Sulfur Mustard Contaminated Skin Defects in the Euthymic Hairless Guinea Pig

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1993-05-13

AD-P008 792 Hyochlorte Solution as a Decossitamrsrl nan Sultur Mustard Contaminated Skin Defects in the Euthymesc Hailess Guinea Pig Mark B. Gol, OVM...euthymic hairles guinea pigs (EHGP) (n--6) were exposed tn 0 4 LD50 HO in a hA-thickntss 8 mm surgical bmop~sy skin deflect (ioe wound) Each animal was...in a animal model of an HO contaminated wound. The euthymic hairless guinea pig (EHGP) has been extensrvely studied and aicepted as the model of

Gene expression in skin tumors induced in hairless mice by chronic exposure to ultraviolet B irradiation

International Nuclear Information System (INIS)

Sato, Hiromi; Tanaka, Misao; Kobayashi, Shizuko; Suzuki, Junko S.; Ogiso, Manabu; Tohyama, Chiharu

1997-01-01

We investigated the expressions of c-Ha-ras, c-jun, c-fos, c-myc genes and p53 protein in the development of skin tumours induced by chronic exposure to UVB without a photosensitizer using hairless mice. When mice were exposed to UVB at a dose of 2 kJ/m 2 three times a week, increased c-Ha-ras and c-myc transcripts were detected after only 5 weeks of exposure, while no tumour appeared on the exposed skin. The increase in gene expression continued until 25 weeks, when tumours, identified pathologically as mainly squamous cell carcinomas (SCC), developed in the dorsal skin. In these SCC, overexpression of c-fos mRNA was also observed along with the increases in c-Ha-ras and c-myc. A single dose of UVB (2 kJ/m 2 ) applied to the backs of hairless mice transiently induced overexpression of the early event genes c-fos, c-jun and c-myc, but not c-Ha-ras, in the exposed area of skin. Accumulation of p53 protein was determined by Western blotting analysis of immunohistochemistry using monoclonal antibodies PAb 240 or 246, which recognize mutant or wide type, respectively. In the SCC, a mutant p53 protein accumulated in the cytoplasm and nucleus. After single-dose irradiation, the increased wild-type p53 protein was observed in the nuclei of epidermal cells. The present results suggest that overexpression of the c-fos, c-myc and c-Ha-ras genes, and the mutational changes in p53 protein might be associated with skin photocarcinogenesis. Moreover, overexpression of the c-Ha-ras and c-myc genes might be an early event in the development of UVB-induced skin tumors in mice. (author)

Metabolic evaluation of skin absorption of tritiated formaldehyde in hairless rats

International Nuclear Information System (INIS)

Trivedi, A.

1993-11-01

Tritiated organics are present as trace impurities in tritium handling facilities. Tritiated formaldehyde has been detected in the atmosphere and gaseous effluents of tritium handling and storage sites. The ability of tritiated formaldehyde to diffuse through the skin is a possible route of intake. Since the metabolism of tritium through this mode of contamination is not currently established, experiments were performed in which tritiated formaldehyde was applied topically on the dorsal skin of hairless rats. These experiments demonstrated that tritium was assimilated and retained in the exposed skin as organically bound tritium (OBT). This retained OBT dominates tritium turnover in the body. OBT retention in the unexposed skin, liver, heart and kidneys was also observed. The loss of tritium from the animals showed that about 10% of the applied tritium was excreted in urine. It is assumed that the rest of the applied activity may have been lost through other excretory pathways, or may not have entered into the body. The biokinetics of tritium excretion is best described by a sum of three exponential functions. Most of the excreted tritium was in the form of OBT (90%) and results in the rapid clearing of OBT in the skin to urine and retention in other tissues. The evaluation of the dose-rate data showed that the dose-rate to exposed skin was almost a magnitude greater than the dose-rate to other organs. (author). 21 refs., 4 tabs., 4 figs

Metabolic evaluation of skin absorption of tritiated formaldehyde in hairless rats

Energy Technology Data Exchange (ETDEWEB)

Trivedi, A

1993-11-01

Tritiated organics are present as trace impurities in tritium handling facilities. Tritiated formaldehyde has been detected in the atmosphere and gaseous effluents of tritium handling and storage sites. The ability of tritiated formaldehyde to diffuse through the skin is a possible route of intake. Since the metabolism of tritium through this mode of contamination is not currently established, experiments were performed in which tritiated formaldehyde was applied topically on the dorsal skin of hairless rats. These experiments demonstrated that tritium was assimilated and retained in the exposed skin as organically bound tritium (OBT). This retained OBT dominates tritium turnover in the body. OBT retention in the unexposed skin, liver, heart and kidneys was also observed. The loss of tritium from the animals showed that about 10% of the applied tritium was excreted in urine. It is assumed that the rest of the applied activity may have been lost through other excretory pathways, or may not have entered into the body. The biokinetics of tritium excretion is best described by a sum of three exponential functions. Most of the excreted tritium was in the form of OBT (90%) and results in the rapid clearing of OBT in the skin to urine and retention in other tissues. The evaluation of the dose-rate data showed that the dose-rate to exposed skin was almost a magnitude greater than the dose-rate to other organs. (author). 21 refs., 4 tabs., 4 figs.

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

Energy Technology Data Exchange (ETDEWEB)

Jain, Anil K.; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Orlicky, David J. [Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Agarwal, Chapla [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); White, Carl W. [Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045USA (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@UCDenver.edu [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States)

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

Effect of repeated ultraviolet irradiation on skin of hairless mice

International Nuclear Information System (INIS)

Alpermann, H.; Vogel, H.G.

1978-01-01

The effect of repeated UV-irradiation on mechanical and biochemical parameters was studied in skin of hairless mice. uV-A irradiation for a period of 1 h daily over 8 weeks caused only a slight increase in skin thickness and a decrease in ultimate strain. The changes induced by UV-B and C, however, were quite remarkable. Skin thickness was increased depending on the daily dose exposure time (15-90 s at an irradiation rate of 20mW/cm 2 UV-B and A and of 14mW/cm 2 UV-C) and the duration of treatment (1-6 weeks). Ultimate load, tensile strength and modulus of elasticity showed an increase following medium dosages after 1 and 2 weeks, however, a decrease after high dosages and longterm treatment. Ultimate strain was found to be the most sensitive parameter being decreased depending on exposure time and duration of treatment. Insoluble collagen and total collagen were decreased after long-term treatment thus being correlated with the mechanical parameters. The elastin content was only barely influenced and not correlated with the mechanical data, e.g. the modulus of elasticity. Thus, a favourable effect of short-treatment with low doses of UV-irradiation of mechanical parameters of skin could be demonstrated. Long-term treatment with relatively high doses of UV-B, however, resulted in unfavourable effects, whereby first ultimate strain, then ultimate load, modulus of elasticity and tensile strength were decreased. (orig.) [de

Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

Science.gov (United States)

Kawano, Ken-Ichi; Umemura, Kazuo

2013-05-01

The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd.

Quantitative measurements of oxidative stress in mouse skin induced by X-ray irradiation

International Nuclear Information System (INIS)

Chi, Cuiping; Tanaka, Ryoko; Okuda, Yohei; Ikota, Nobuo; Ozawa, Toshihiko; Anzai, Kazunori; Yamamoto, Haruhiko; Urano, Shiro

2005-01-01

To find efficient methods to evaluate oxidative stress in mouse skin caused by X-ray irradiation, several markers and methodologies were examined. Hairless mice were irradiated with 50 Gy X-rays and skin homogenates or skin strips were prepared. Lipid peroxidation was measured using the skin homogenate as the level of thiobarbituric acid reactive substances. The level of lipid peroxidation increased with time after irradiation and was twice that of the control at 78 h. Electron spin resonance (ESR) spectra of skin strips showed a clear signal for the ascorbyl radical, which increased with time after irradiation in a manner similar to that of lipid peroxidation. To measure levels of glutathione (GSH) and its oxidized forms (GSSG) simultaneously, two high performance liquid chromatography (HPLC) methods, sample derivatization with 1-fluoro-2,4-dinitrobenzene and detection with a UV detector (method A) and no derivatization and detection with an electrochemical detector (method B), were compared and the latter was found to be better. No significant change was observed within 24 h after irradiation in the levels of GSH and GSSG measured by method B. The GSH/GSSG ratio may be a less sensitive parameter for the evaluation of acute oxidative stress caused by X-ray irradiation in the skin. Monitoring the ascorbyl radical seems to be a good way to evaluate oxidative stress in skin in vivo. (author)

Transdermal delivery of naltrexol and skin permeability lifetime after microneedle treatment in hairless guinea pigs.

Science.gov (United States)

Banks, Stan L; Pinninti, Raghotham R; Gill, Harvinder S; Paudel, Kalpana S; Crooks, Peter A; Brogden, Nicole K; Prausnitz, Mark R; Stinchcomb, Audra L

2010-07-01

Controlled-release delivery of 6-beta-naltrexol (NTXOL), the major active metabolite of naltrexone, via a transdermal patch is desirable for treatment of alcoholism. Unfortunately, NTXOL does not diffuse across skin at a therapeutic rate. Therefore, the focus of this study was to evaluate microneedle (MN) skin permeation enhancement of NTXOL's hydrochloride salt in hairless guinea pigs. Specifically, these studies were designed to determine the lifetime of MN-created aqueous pore pathways. MN pore lifetime was estimated by pharmacokinetic evaluation, transepidermal water loss (TEWL) and visualization of MN-treated skin pore diameters using light microscopy. A 3.6-fold enhancement in steady-state plasma concentration was observed in vivo with MN treated skin with NTXOL.HCl, as compared to NTXOL base. TEWL measurements and microscopic evaluation of stained MN-treated guinea pig skin indicated the presence of pores, suggesting a feasible nonlipid bilayer pathway for enhanced transdermal delivery. Overall, MN-assisted transdermal delivery appears viable for at least 48 h after MN-application. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association

Prevention of short-term ultraviolet B radiation-mediated damages by resveratrol in SKH-1 hairless mice

International Nuclear Information System (INIS)

Afaq, Farrukh; Adhami, Vaqar Mustafa; Ahmad, Nihal

2003-01-01

Nonmelanoma skin cancer is the most common cancer among humans and solar UV radiation, particularly its UVB component (290-320 nm), is its major cause. One way to reduce the occurrence of the cancer is via the use of substances (often antioxidants) termed 'photochemopreventive agents'. Resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin found in grapes, nuts, fruits, and red wine, is a potent antioxidant with strong anti-inflammatory and antiproliferative properties. This study was designed to examine whether resveratrol possesses the potential to ameliorate the damages caused by short-term UVB exposure to mouse skin. Single topical application of resveratrol (25 μmol/0.2 ml acetone per mouse) to SKH-1 hairless mice was found to result in significant inhibition of UVB (180 mJ/cm 2 )-mediated increase in bifold skin thickness and skin edema. The resveratrol treatment to mouse skin was also found to result in significant inhibition of UVB-mediated induction of cyclooxygenase and ornithine decarboxylase (ODC) enzyme activities and protein expression of ODC, which are well-established markers for tumor promotion. We also observed that resveratrol inhibits UVB-mediated increased level of lipid peroxidation, a marker of oxidative stress. Taken together, our results suggest that resveratrol may afford substantial protection against the damages caused by UVB exposure, and these protective effects may be mediated via its antioxidant properties

Thread Embedding Acupuncture Inhibits Ultraviolet B Irradiation-Induced Skin Photoaging in Hairless Mice

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Yoon-Jung Kim

2015-01-01

Full Text Available Thread embedding acupuncture (TEA is an acupuncture treatment applied to many diseases in Korean medical clinics because of its therapeutic effects by continuous stimulation to tissues. It has recently been used to enhance facial skin appearance and antiaging, but data from evidence-based medicine are limited. To investigate whether TEA therapy can inhibit skin photoaging by ultraviolet B (UVB irradiation, we performed analyses for histology, histopathology, in situ zymography and western blot analysis in HR-1 hairless mice. TEA treatment resulted in decreased wrinkle formation and skin thickness (Epidermis; P=0.001 versus UV in UVB irradiated mice and also inhibited degradation of collagen fibers (P=0.010 versus normal by inhibiting proteolytic activity of gelatinase matrix-metalloproteinase-9 (MMP-9. Western blot data showed that activation of c-Jun N-terminal kinase (JNK induced by UVB (P=0.002 versus normal group was significantly inhibited by TEA treatment (P=0.005 versus UV with subsequent alleviation of MMP-9 activation (P=0.048 versus UV. These results suggest that TEA treatment can have anti-photoaging effects on UVB-induced skin damage by maintenance of collagen density through regulation of expression of MMP-9 and related JNK signaling. Therefore, TEA therapy may have potential roles as an alternative treatment for protection against skin damage from aging.

The Standardized Extract of Juniperus communis Alleviates Hyperpigmentation in Vivo HRM-2 Hairless Mice and in Vitro Murine B16 Melanoma Cells.

Science.gov (United States)

Jegal, Jonghwan; Chung, Ki Wung; Chung, Hae Young; Jeong, Eun Ju; Yang, Min Hye

2017-01-01

In European folk medicine, the fruits of Juniperus communis are used in the treatment of skin-related disorders such as skin infection, itching, and psoriasis. Previously, we reported that the EtOAc fraction of J. communis (EAJC) contained tyrosinase inhibition properties in vitro non-cellular experiment. The aim of this study was to evaluate anti-melanogenic effect of standardized EAJC on a hyperpigmentation animal model. Therapeutic effects of EAJC toward skin hyperpigmentation were confirmed by both in vivo experiment and in vitro cell-based assay. Skin depigmenting effect was detected by topical treatment of EAJC for 11 d to HRM-2 melanin-possessing hairless mice. Histologic findings including significantly decreased melanin depositions could be observed in dorsal skin samples of EAJC-treated group. In addition, the EAJC (50 µg/mL) attenuated melanin production through down-regulation of tyrosinase activity and protein expression in B16 murine melanoma cells. According to the phytochemical analysis, EAJC was found to contain hypolaetin-7-O-β-D-xylopyranoside and isoscutellarein-7-O-β-D-xylopyranoside as main components. Hypolaetin-7-O-β-D-xylopyranoside was responsible for the skin-lightening effect of EAJC by reducing the number of melanocytes in dorsal skins of HRM-2 mice. The present study provided direct experimental evidence for skin-lightening effect of EAJC in UV-irradiated hairless mouse model. Therapeutic attempts with the J. communis might be useful in the management of skin pigmentation-related diseases.

Skin penetration and retention of L-ascorbic acid 2-phosphate using multilamellar vesicles.

Science.gov (United States)

Yoo, Juno; Shanmugam, Srinivasan; Song, Chung-Kil; Kim, Dae-Duk; Choi, Han-Gon; Yong, Chul-Soon; Woo, Jong-Soo; Yoo, Bong Kyu

2008-12-01

Transdermal formulation of L-ascorbic acid 2-phosphate magnesium salt (A2P) was prepared using multilamellar vesicles (MLV). A2P was either physically mixed with or entrapped into three different MLVs of neutral, cationic, and anionic liposome vesicles. For the preparation of neutral MLVs, phosphatidylcholine (PC) and cholesterol (CH) were used. For cationic and anionic MLVs, dioleoyl-trimethylammonium-propane and dimyristoyl glycerophosphate were added as surface charge inducers, respectively, in addition to PC and CH. Particle size of the three A2P-loaded MLVs was submicron, and polydispersity index revealed homogenous distribution of the prepared MLVs except neutral ones. Skin penetration study with hairless mouse skin showed that both physical mixtures of A2P with empty MLVs and A2P-loaded MLVs increased penetration of the drug compared to aqueous A2P solution. During the penetration, however, significant amount of the drug was metabolized into L-ascorbic acid, which has no beneficial effect on stimulation of hair growth. Out of the physical mixtures and A2P-loaded MLVs tested, physical mixture of A2P with empty cationic MLV resulted in the greatest skin penetration and retention in hairless mouse skin.

Detection of genomic signatures for pig hairlessness using high-density SNP data

Directory of Open Access Journals (Sweden)

Ying SU,Yi LONG,Xinjun LIAO,Huashui AI,Zhiyan ZHANG,Bin YANG,Shijun XIAO,Jianhong TANG,Wenshui XIN,Lusheng HUANG,Jun REN,Nengshui DING

2014-12-01

Full Text Available Hair provides thermal regulation for mammals and protects the skin from wounds, bites and ultraviolet (UV radiation, and is important in adaptation to volatile environments. Pigs in nature are divided into hairy and hairless, which provide a good model for deciphering the molecular mechanisms of hairlessness. We conducted a genomic scan for genetically differentiated regions between hairy and hairless pigs using 60K SNP data, with the aim to better understand the genetic basis for the hairless phenotype in pigs. A total of 38405 SNPs in 498 animals from 36 diverse breeds were used to detect genomic signatures for pig hairlessness by estimating between-population (FST values. Seven diversifying signatures between Yucatan hairless pig and hairy pigs were identified on pig chromosomes (SSC 1, 3, 7, 8, 10, 11 and 16, and the biological functions of two notable genes, RGS17 and RB1, were revealed. When Mexican hairless pigs were contrasted with hairypigs, strong signatures were detected on SSC1 and SSC10, which harbor two functionally plausible genes, REV3L and BAMBI. KEGG pathway analysis showed a subset of overrepresented genes involved in the T cell receptor signaling pathway, MAPK signaling pathway and the tight junction pathways. All of these pathways may be important in local adaptability of hairless pigs. The potential mechanisms underlying the hairless phenotype in pigs are reported for the first time. RB1 and BAMBI are interesting candidate genes for the hairless phenotype in Yucatan hairless and Mexico hairless pigs, respectively. RGS17, REV3L, ICOS and RASGRP1 as well as other genes involved in the MAPK and T cell receptor signaling pathways may be important in environmental adaption by improved tolerance to UV damage in hairless pigs. These findings improve our understanding of the genetic basis for inherited hairlessness in pigs.

Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice

International Nuclear Information System (INIS)

Uddin, Ahmed N.; Burns, Fredric J.; Rossman, Toby G.; Chen, Haobin; Kluz, Thomas; Costa, Max

2007-01-01

The skin cancer enhancing effect of chromium (in male mice) and nickel in UVR-irradiated female Skh1 mice was investigated. The dietary vitamin E and selenomethionine were tested for prevention of chromium-enhanced skin carcinogenesis. The mice were exposed to UVR (1.0 kJ/m 2 3x weekly) for 26 weeks either alone, or combined with 2.5 or 5.0 ppm potassium chromate, or with 20, 100 or 500 ppm nickel chloride in drinking water. Vitamin E or selenomethionine was added to the lab chow for 29 weeks beginning 3 weeks before the start of UVR exposure. Both chromium and nickel significantly increased the UVR-induced skin cancer yield in mice. In male Skh1 mice, UVR alone induced 1.9 ± 0.4 cancers/mouse, and 2.5 or 5.0 ppm potassium chromate added to drinking water increased the yields to 5.9 ± 0.8 and 8.6 ± 0.9 cancers/mouse, respectively. In female Skh1 mice, UVR alone induced 1.7 ± 0.4 cancers/mouse, and the addition of 20, 100 or 500 ppm nickel chloride increased the yields to 2.8 ± 0.9, 5.6 ± 0.7 and 4.2 ± 1.0 cancers/mouse, respectively. Neither vitamin E nor selenomethionine reduced the cancer yield enhancement by chromium. These results confirm that chromium and nickel, while not good skin carcinogens per se, are enhancers of UVR-induced skin cancers in Skh1 mice. Data also suggest that the enhancement of UVR-induced skin cancers by chromate may not be oxidatively mediated since the antioxidant vitamin E as well as selenomethionine, found to prevent arsenite-enhanced skin carcinogenesis, failed to suppress enhancement by chromate

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

Science.gov (United States)

Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

1998-01-23

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

Carcinogenic effect of sequential artificial sunlight and UV-A irradiation in hairless mice. Consequences for solarium 'therapy'

International Nuclear Information System (INIS)

Staberg, B.; Wulf, H.C.; Poulsen, T.; Klemp, P.; Brodthagen, H.

1983-01-01

The carcinogenic effect of artificial UV sunlight followed by UV-A irradiation in human solaria doses has been studied with the use of the hairless mouse as an animal model. Artificial sunlight exposure alone induced only a moderate skin tumor incidence (animals with at least one tumor) of 0.15 after one year, and UV-A irradiation alone induced no tumor formation. However, the combination of artificial sunlight exposure and subsequent UV-A irradiation significantly increased the tumor incidence to 0.72. We conclude that, in humans, tanning with UV-A for cosmetic purposes may not be an innocuous procedure

Ability of PABA to protect mammalian skin from ultraviolet light-induced skin tumors and actinic damage

International Nuclear Information System (INIS)

Snyder, D.S.; May, M.

1975-01-01

Application of 5% para-aminobenzoic acid (PABA) to hairless mice one hour prior to ultraviolet light (UVL) irradiation will almost totally protect these animals from developing tumors induced by chronic exposure to UVL in the 290 to 320 nm range in conjunction with a chemical carcinogen. Mice exposed to UVL and not protected by PABA developed primarily squamous cell carcinomas. Two months after cessation of chronic UVL exposure, the non-PABA-treated irradiated mouse skin appeared thickened, yellow, and wrinkled while showing elevated DNA synthesis, hyperplasia, hypergranulosis, and increased amounts of elastotic material. The PABA-treated skin was grossly normal

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

International Nuclear Information System (INIS)

Wheeler, D. L.; Verma, A. K.; Denning, M. F.

2013-01-01

The multistep model of mouse skin carcinogenesis has facilitated identification of irreversible genetic events of initiation and progression, and epigenetic events of tumor promotion. Mouse skin tumor initiation can be accomplished by a single exposure to a sufficiently small dose of a carcinogen, and this step is rapid and irreversible. However, promotion of skin tumor formation requires a repeated and prolonged exposure to a promoter, and that tumor promotion is reversible. Investigations focused on the mechanisms of mouse carcinogenesis have resulted in the identifications of potential molecular targets of cancer induction and progression useful in planning strategies for human cancer prevention trials. This special issue contains eight papers that focus on mouse models used to study individual proteins expressed in the mouse skin and the role they play in differentiation, tissue homeostasis, skin carcinogenesis, and chemo prevention of skin cancer.

Safety evaluation of stamp type digital microneedle devices in hairless mice.

Science.gov (United States)

Park, Kui Young; Jang, Woo Sun; Lim, Yun Young; Ahn, Joo Hee; Lee, Sang Jin; Kim, Chan Woong; Kim, Sung Eun; Kim, Beom Joon; Kim, Myeung Nam

2013-02-01

Microneedles provide a minimally invasive means to transport molecules into the skin. A number of specific strategies have been employed to use microneedles for transdermal delivery. The purpose of this study was to investigate the safety of two new digital microneedle devices (Digital Hand® and Digital Pro®; Bomtech Electronics Co., Ltd., Seoul, Korea) for the perforation of skin in skin-hairless-1 mice. This device replaces conventional needles and is designed specifically for intradermal delivery. We used two newly developed digital microneedle devices to perforate the skin of skin-hairless-1 mice. We conducted a comparative study of the two digital microneedle devices and DTS® (Disk type-microneedle Therapy System; DTS lab., Seoul, Korea). To evaluate skin stability, we performed visual and dermatoscopic inspections, measurements of transepidermal water loss, and biopsies. The two novel digital microneedle devices did not induce significant abnormalities of the skin on visual or dermatoscopic inspection, regardless of needle size (0.25~2.0 mm). No significant histopathological changes, such as inflammatory cell infiltration, desquamation of the stratum corneum, or disruption of the basal layer, were observed. The digital microneedle devices and microneedle therapy system produced similar results on measures of skin stability. These two novel digital microneedle devices are safe transdermal drug delivery systems.

The sunburn cell in hairless mouse epidermis: quantitative studies with UV-A radiation and mono- and bifunctional psoralens

International Nuclear Information System (INIS)

Young, A.R.; Magnus, I.A.

1982-01-01

The production of the sunburn cell by UV-A radiation and topical psoralens in hairless mouse epidermis has been studied. It has been shown that the appearance of this cell is dependent on the dose of both UV-A radiation and of the psoralen. The time-course with 8-methoxypsoralen has peak sunburn cell numbers at 28 hr postirradiation. A comparison of 2 bifunctional (8-methoxypsoralen and 5-methoxypsoralen) and 2 monofunctional (angelicin and 3-carbethoxypsoralen) psoralens showed the former are more potent. This suggests that DNA crosslink lesions may play a rle in sunburn cell production

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

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

2011-03-01

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/cm(2), 746.32 ± 12.43 µg/cm(2), and 1882 ± 395.18 µg/cm(2), 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/cm(2) and 746.32 ± 12.43 µg/cm(2) while without prewash, the 24-h HC released from topical gel was 67.2 ± 7.41 µg/cm(2) and 653.43 ± 85.62 µg/cm(2) 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.

Curcumin Protects against UVB-Induced Skin Cancers in SKH-1 Hairless Mouse: Analysis of Early Molecular Markers in Carcinogenesis

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Kuen-Daw Tsai

2012-01-01

Full Text Available Curcumin (CUR has been shown to possess a preventive effect against various cancers and interfere with multiple-cell signaling pathways. We evaluated the protective effects of CUR in regression of UVB-induced skin tumor formation in SKH-1 hairless mice and its underlying early molecular biomarkers associated with carcinogenesis. Mice irradiated with UVB at 180 mJ/cm2 twice per week elicited 100% tumor incidence at 20 weeks. Topical application of CUR prior to UVB irradiation caused delay in tumor appearance, multiplicity, and size. Topical application of CUR prior to and immediately after a single UVB irradiation (180 mJ/cm2 resulted in a significant decrease in UVB-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells together with an increase in p53 and p21/Cip1-positive cell population in epidermis. Simultaneously, CUR also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2, prostaglandin E2 (PGE2, and nitric oxide (NO levels. The results suggest that the protective effect of CUR against photocarcinogenesis is accompanied by downregulation of cell proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-κB, and of inflammatory responses involving COX-2, PGE2, and NO, while upregulation of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair.

Protective effect of indole-3-pyruvate against ultraviolet b-induced damage to cultured HaCaT keratinocytes and the skin of hairless mice.

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Reiji Aoki

Full Text Available Previous investigations demonstrated that pyruvate protects human keratinocytes against cell damage stemming from exposure to ultraviolet B (UVB radiation. This study endeavoured to elucidate the protective capacity of aromatic pyruvates (e.g., phenylpyruvate (PPyr, 4-hydroxyphenylpyruvate (HPPyr, and indole-3-pyruvate (IPyr against UVB-induced injury to skin cells, both in vitro and in vivo. Cultured human HaCaT keratinocytes were irradiated with UVB light (60 mJ/cm2 and maintained with or without test compounds (1-25 mM.In addition, the dorsal skin of hairless mice (HR-1 was treated with test compounds (10 μmol and exposed to UVB light (1 J/cm2 twice [corrected]. The ability of the test compounds to ameliorate UVB-induced cytotoxicity and inflammation was then assessed. Aromatic pyruvates reduced cytotoxicity in UVB-irradiated HaCaT keratinocytes, and also diminished the expression of interleukin 1β (IL-1β and interleukin 6 (IL-6. IPyr was more efficacious than either PPyr or HPPyr. Furthermore, only IPyr inhibited cyclooxygenase-2 (Cox-2 expression at both the mRNA and the protein level in UVB-treated keratinocytes. Topical application of IPyr to the dorsal skin of hairless mice reduced the severity of UVB-induced skin lesions, the augmentation of dermal thickness, and transepithelial water loss. Overproduction of IL-1β and IL-6 in response to UVB radiation was also suppressed in vivo by the topical administration of IPyr. These data strongly suggest that IPyr might find utility as a UVB-blocking reagent in therapeutic strategies to lessen UVB-induced inflammatory skin damage.

Effects of a turmeric extract (Curcuma longa) on chronic ultraviolet B irradiation-induced skin damage in melanin-possessing hairless mice.

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Sumiyoshi, Maho; Kimura, Yoshiyuki

2009-12-01

Turmeric (the rhizomes of Curcuma longa L., Zingiberacease) is widely used as a dietary pigment and spice, and has been traditionally used for the treatment of inflammation, skin wounds and hepatic disorders in Ayurvedic, Unani and Chinese medicine. Although the topical application or oral administration of turmeric is used to improve skin trouble, there is no evidence to support this effect. The aim of this study was to clarify whether turmeric prevents chronic ultraviolet B (UVB)-irradiated skin damage. We examined the effects of a turmeric extract on skin damage including changes in skin thickness and elasticity, pigmentation and wrinkling caused by long-term, low-dose ultraviolet B irradiation in melanin-possessing hairless mice. The extract (at 300 or 1000 mg/kg, twice daily) prevented an increase in skin thickness and a reduction in skin elasticity induced by chronic UVB exposure. It also prevented the formation of wrinkles and melanin (at 1000 mg/kg, twice daily) as well as increases in the diameter and length of skin blood vessels and in the expression of matrix metalloproteinase-2 (MMP-2). Prevention of UVB-induced skin aging by turmeric may be due to the inhibition of increases in MMP-2 expression caused by chronic irradiation.

Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice

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Mouret, Stéphane, E-mail: stephane.mouret@irba.fr [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Nguon, Nina; Cléry-Barraud, Cécile [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Dorandeu, Frédéric [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France); Ecole du Val-de-Grâce, 1 place Alphonse Laveran, Paris (France); Boudry, Isabelle [Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche (France)

2013-10-15

Lewisite is a potent chemical warfare arsenical vesicant that can cause severe skin lesions. Today, lewisite exposure remains possible during demilitarization of old ammunitions and as a result of deliberate use. Although its cutaneous toxicity is not fully elucidated, a specific antidote exists, the British anti-lewisite (BAL, dimercaprol) but it is not without untoward effects. Analogs of BAL, less toxic, have been developed such as meso-2,3-dimercaptosuccinic acid (DMSA) and have been employed for the treatment of heavy metal poisoning. However, efficacy of DMSA against lewisite-induced skin lesions remains to be determined in comparison with BAL. We have thus evaluated in this study the therapeutic efficacy of BAL and DMSA in two administration modes against skin lesions induced by lewisite vapor on SKH-1 hairless mice. Our data demonstrate a strong protective efficacy of topical application of dimercapto-chelating agents in contrast to a subcutaneous administration 1 h after lewisite exposure, with attenuation of wound size, necrosis and impairment of skin barrier function. The histological evaluation also confirms the efficacy of topical application by showing that treatments were effective in reversing lewisite-induced neutrophil infiltration. This protective effect was associated with an epidermal hyperplasia. However, for all the parameters studied, BAL was more effective than DMSA in reducing lewisite-induced skin injury. Together, these findings support the use of a topical form of dimercaprol-chelating agent against lewisite-induced skin lesion within the first hour after exposure to increase the therapeutic management and that BAL, despite its side-effects, should not be abandoned. - Highlights: • Topically applied dimercapto-chelating agents reduce lewisite-induced skin damage. • One topical application of BAL or DMSA is sufficient to reverse lewisite effects. • Topical BAL is more effective than DMSA to counteract lewisite-induced skin damage.

Effects of the nonsugar fraction of brown sugar on chronic ultraviolet B irradiation-induced photoaging in melanin-possessing hairless mice.

Science.gov (United States)

Sumiyoshi, Maho; Hayashi, Teruaki; Kimura, Yoshiyuki

2009-04-01

Brown sugar has been used traditionally for the treatment of skin trouble as a component of soaps or lotions. Symptoms of aging including wrinkles and pigmentation develop earlier in sun-exposed skin than unexposed skin, a phenomenon referred to as photoaging. Ultraviolet B (UVB) radiation is one of the most important environmental factors influencing photoaging. The aim of this study was to clarify whether the nonsugar fraction of brown sugar prevents chronic UVB-induced aging of the skin using melanin-possessing hairless mice. The nonsugar fraction (1% or 3% solution, 50 mul/mouse) was applied topically to the dorsal region every day for 19 weeks. Both solutions prevented an increase in skin thickness and reduction in skin elasticity caused by the UVB. The 3% solution also prevented wrinkles and melanin pigmentation as well as increases in the diameter and length of skin blood vessels. Increases in the expression of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in UVB-irradiated skin was inhibited by the nonsugar fraction. Prevention of UVB-induced aging of the skin by topical application of the nonsugar fraction of brown sugar may be due to inhibition of increases in MMP-2 and VEGF expression.

PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas.

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Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E; Havighurst, Thomas C; Kim, KyungMann; Oberley, Terry D; Verma, Ajit K

2010-01-01

Chronic exposure to UVR is the major etiologic factor in the development of human skin cancers including squamous-cell carcinoma (SCC). We have previously shown that protein Kinase C epsilon (PKCepsilon) transgenic mice on FVB/N background, which overexpress PKCepsilon protein approximately eightfold over endogenous levels in epidermis, exhibit about threefold more sensitivity than wild-type littermates to UVR-induced development of SCC. To determine whether it is PKCepsilon and not the mouse genetic background that determines susceptibility to UVR carcinogenesis, we cross-bred PKCepsilon FVB/N transgenic mice with SKH-1 hairless mice to generate PKCepsilon-overexpressing SKH-1 hairless mice. To evaluate the susceptibility of PKCepsilon SKH-1 hairless transgenic mice to UVR carcinogenesis, the mice were exposed to UVR (1-2 KJ m(-2)) three times weekly from a bank of six kodacel-filtered FS40 sunlamps. As compared with the wild-type hairless mice, PKCepsilon overexpression in SKH-1 hairless mice decreased the latency (12 weeks), whereas it increased the incidence (twofold) and multiplicity (fourfold) of SCC. The SKH hairless transgenic mice were observed to be as sensitive as FVB/N transgenic mice to UVR-induced development of SCC and expression of proliferative markers (proliferating cell nuclear antigen, signal transducers and activators of transcription 3, and extracellular signal-regulated kinase 1/2). The results indicate that PKCepsilon level dictates susceptibility, irrespective of genetic background, to UVR carcinogenesis.

Photoprotective effects of sulindac against ultraviolet B-induced phototoxicity in the skin of SKH-1 hairless mice

International Nuclear Information System (INIS)

Athar, Mohammad; An, Kathy P.; Tang Xiuwei; Morel, Kimberly D.; Kim, Arianna L.; Kopelovich, Levy; Bickers, David R.

2004-01-01

Sulindac is a nonsteroidal anti-inflammatory drug with demonstrated potency as a chemopreventive agent in animal models of carcinogenesis and in patients with familial adenomatous polyposis. Because tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that anti-inflammatory agents may have potent antitumor effects. In human skin, sulindac reduces bradykinin-induced edema. In this study, we tested the hypothesis that the cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced injury that is crucial for the induction of cancer. Exposure of SKH-1 hairless mice to two consecutive doses of UVB (230 mJ/cm 2 ) induces various inflammatory responses including erythema, edema, epidermal hyperplasia, infiltration of polymorphonuclear leukocytes, etc. Topical application of sulindac (1.25-5.0 mg/0.2 ml acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or immediately after UVB exposure substantially inhibited these inflammatory responses in a dose-dependent manner. Oral administration of sulindac in drinking water (160 ppm) for 15 days before and during UVB irradiation similarly reduced these inflammatory responses. These potent anti-inflammatory effects of sulindac suggested the possibility that the drug could inhibit signaling processes that relate to carcinogenic insult by UVB. Accordingly, studies were conducted to assess the efficacy of sulindac in attenuating the expression of UVB-induced early surrogate molecular markers of photodamage and carcinogenesis. UVB exposure enhanced the expression of p53, c-fos, cyclins D1 and A, and PCNA 24 h after irradiation. Treatment of animals with either topical or oral administration of sulindac largely abrogated the expression of these UVB-induced surrogate markers. These results indicate that the cyclooxygenase inhibitor sulindac is effective in reducing UVB-induced events relevant to carcinogenesis and that this category of topically applied or

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

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Vaid, Mudit; Singh, Tripti; Prasad, Ram [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Katiyar, Santosh K., E-mail: skatiyar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294 (United States); Birmingham Veterans Affairs Medical Center, Birmingham, AL 35294 (United States)

2014-01-01

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm{sup 2}) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (P < 0.01), and PGE{sub 2} receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser{sup 473} in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors. - Highlights: • Consumption of high-fat diet increases UVB-induced skin tumor development in mice. • Intake of high-fat diet stimulates progression of UV-induced papilloma to carcinoma. • Intake of high-fat diet enhances inflammation in UV-exposed skin • Regular

Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice†

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Pal, Harish Chandra; Athar, Mohammad; Elmets, Craig A.; Afaq, Farrukh

2014-01-01

Solar ultraviolet B (UVB) radiation has been shown to induce inflammation, DNA damage, p53 mutations, and alterations in signaling pathways eventually leading to skin cancer. In the present study, we investigated whether fisetin reduces inflammatory responses and modulates PI3K/AKT/NFκB cell survival signaling pathways in UVB exposed SKH-1 hairless mouse skin. Mice were exposed to 180 mJ/cm2 of UVB radiation on alternate days for a total of seven exposures, and fisetin (250 and 500 nmol) was applied topically after 15 min of each UVB exposure. Fisetin treatment to UVB exposed mice resulted in decreased hyperplasia and reduced infiltration of inflammatory cells. Fisetin treatment also reduced inflammatory mediators such as COX-2, PGE2 as well as its receptors (EP1- EP4), and MPO activity. Furthermore, fisetin reduced the level of inflammatory cytokines TNFα, IL-1β and IL-6 in UVB exposed skin. Fisetin treatment also reduced cell proliferation markers as well as DNA damage as evidenced by increased expression of p53 and p21 proteins. Further studies revealed that fisetin inhibited UVB-induced expression of PI3K, phosphorylation of AKT, and activation of the NFκB signaling pathway in mouse skin. Overall, these data suggest that fisetin may be useful against UVB-induced cutaneous inflammation and DNA damage. PMID:25169110

Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/AKT/NFκB signaling pathways in SKH-1 hairless mice.

Science.gov (United States)

Pal, Harish Chandra; Athar, Mohammad; Elmets, Craig A; Afaq, Farrukh

2015-01-01

Solar ultraviolet B (UVB) radiation has been shown to induce inflammation, DNA damage, p53 mutations and alterations in signaling pathways eventually leading to skin cancer. In this study, we investigated whether fisetin reduces inflammatory responses and modulates PI3K/AKT/NFκB cell survival signaling pathways in UVB-exposed SKH-1 hairless mouse skin. Mice were exposed to 180 mJ cm(-2) of UVB radiation on alternate days for a total of seven exposures, and fisetin (250 and 500 nmol) was applied topically after 15 min of each UVB exposure. Fisetin treatment to UVB-exposed mice resulted in decreased hyperplasia and reduced infiltration of inflammatory cells. Fisetin treatment also reduced inflammatory mediators such as COX-2, PGE2 as well as its receptors (EP1-EP4) and MPO activity. Furthermore, fisetin reduced the level of inflammatory cytokines TNFα, IL-1β and IL-6 in UVB-exposed skin. Fisetin treatment also reduced cell proliferation markers as well as DNA damage as evidenced by increased expression of p53 and p21 proteins. Further studies revealed that fisetin inhibited UVB-induced expression of PI3K, phosphorylation of AKT and activation of the NFκB signaling pathway in mouse skin. Overall, these data suggest that fisetin may be useful against UVB-induced cutaneous inflammation and DNA damage. © 2014 The American Society of Photobiology.

Oral nanotherapeutics: Redox nanoparticles attenuate ultraviolet B radiation-induced skin inflammatory disorders in Kud:Hr- hairless mice.

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Feliciano, Chitho P; Nagasaki, Yukio

2017-10-01

The active participation of an anti-inflammatory drug in the biological pathways of inflammation is crucial for the achievement of beneficial and therapeutic effects. This study demonstrated the development of redox nanoparticles that can circulate in the blood at significantly high levels, thus increasing their efficacy as an oral treatment against the deleterious effects of reactive oxygen species (ROS) in an in vivo inflammatory skin model. To confirm the blood bioavailability of the nanoparticles, mice were injected with the nanoparticles solution (RNP N ) via oral gavage. Using electron spin resonance and radioactive labeling techniques, the blood circulation of the redox polymer that forms the nanoparticles was confirmed 24 h after oral administration. This contrasted with its low molecular weight counterpart (NH 2 -TEMPO), which peaked 15 min post injection and was found to be cleared rapidly within minutes after the peak. We then tested its efficacy in the inflammatory skin model. Kud:Hr-hairless mice were irradiated with UVB (302 nm) to induce skin damage and inflammation. Throughout the entire period of UVB irradiation, RNP N was administered to mice by free drinking. NH 2 -TEMPO was used as the control. The results showed that oral supplementation of RNP N significantly improved the therapeutic effects of the core nitroxide radical compared with its low molecular weight counterpart. Furthermore, RNP N significantly reduced UVB-induced skin aging, epidermal thickening, edema, erythema, skin lesions, and various pathological skin inflammatory disorders in vivo. From the obtained data, we concluded that the use of long-circulating redox nanoparticles (RNP N ) provided an effective treatment against the damaging effects of excessive ROS in the body. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metabolism of skin-absorbed resveratrol into its glucuronized form in mouse skin.

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Itsuo Murakami

Full Text Available Resveratrol (RESV is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV.

Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice

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Po-Yuan Wu

2017-10-01

Full Text Available Chronic ultraviolet (UV exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin’s antiphotodamage and antiphotoinflammation activities.

Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice.

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Wu, Po-Yuan; Lyu, Jia-Ling; Liu, Yi-Jung; Chien, Ting-Yi; Hsu, Hao-Cheng; Wen, Kuo-Ching; Chiang, Hsiu-Mei

2017-10-10

Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs) activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values) and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin's antiphotodamage and antiphotoinflammation activities.

Hyperelastic Material Properties of Mouse Skin under Compression.

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Yuxiang Wang

Full Text Available The skin is a dynamic organ whose complex material properties are capable of withstanding continuous mechanical stress while accommodating insults and organism growth. Moreover, synchronized hair cycles, comprising waves of hair growth, regression and rest, are accompanied by dramatic fluctuations in skin thickness in mice. Whether such structural changes alter skin mechanics is unknown. Mouse models are extensively used to study skin biology and pathophysiology, including aging, UV-induced skin damage and somatosensory signaling. As the skin serves a pivotal role in the transfer function from sensory stimuli to neuronal signaling, we sought to define the mechanical properties of mouse skin over a range of normal physiological states. Skin thickness, stiffness and modulus were quantitatively surveyed in adult, female mice (Mus musculus. These measures were analyzed under uniaxial compression, which is relevant for touch reception and compression injuries, rather than tension, which is typically used to analyze skin mechanics. Compression tests were performed with 105 full-thickness, freshly isolated specimens from the hairy skin of the hind limb. Physiological variables included body weight, hair-cycle stage, maturity level, skin site and individual animal differences. Skin thickness and stiffness were dominated by hair-cycle stage at young (6-10 weeks and intermediate (13-19 weeks adult ages but by body weight in mature mice (26-34 weeks. Interestingly, stiffness varied inversely with thickness so that hyperelastic modulus was consistent across hair-cycle stages and body weights. By contrast, the mechanics of hairy skin differs markedly with anatomical location. In particular, skin containing fascial structures such as nerves and blood vessels showed significantly greater modulus than adjacent sites. Collectively, this systematic survey indicates that, although its structure changes dramatically throughout adult life, mouse skin at a given

Studies on the relationship between epidermal cell turnover kinetics and permeability of hairless mouse skin

International Nuclear Information System (INIS)

Han, S.R.

1988-01-01

The primary aim of this study was to develop non-invasive, physical means to quantitatively assess the epidermal turnover kinetics and barrier properties of the skin and relate these to the cutaneous irritation which results from ultraviolet light irradiation and mold thermal burns. After systematically injecting radiolabeled glycine, the appearance of radioactivity at the skin's surface indicated the transit time of radiolabeled cells through the skin. By plotting the data as the cumulative specific activity against time and then fitting them with a third order polynomial equation, it is possible to estimate the turnover time of the stratum corneum. The skin turnover was coordinated with non-invasive transepidermal water loss (TEWL) studies determined with an evaporimeter. In vitro diffusion studies of the permeability of hydrocortisone through UVB irradiated and thermally burned skin were also performed. The studies indicated that irritated skin offers a relatively low diffusional resistance to hydrocortisone. Depending on the severity of the trauma, the increases in hydrocortisone's permeability coefficient through irritated skin ranged from a low of about 2 times normal to a high of about 210 times normal. Trauma-induced changes in hydrocortisone permeability parallel changes in TEWL, proving that the barrier deficient state resulting from rapid epidermal turnover is a general phenomenon

EPR detection of free radicals in UV-irradiated skin: mouse versus human

International Nuclear Information System (INIS)

Jurkiewicz, B.A.; Buettner, G.R.

1996-01-01

Ultraviolet radiation produces free radicals in Skh-1 mouse skin, contributing to photoaging and carcinogenesis. If a mouse model is a general indicator of free radical processes in human skin photobiology, then radical production observed in mouse and human skin should be directly comparative. In this work we show that UV radiation (λ > 300 nm, 14 μW/cm 2 UVB; 3.5 mW/cm 2 UVA) increases the ascorbate free radical (Asc) electron paramagnetic resonance (EPR) signal in both Skh-1 mouse skin (45%) and human facial skin biopsies (340%). Visible light (λ > 400 nm; 0.23 mW/cm 2 UVA) also increased the Ascsignal in human skin samples (45%) but did not increase baseline mouse Asc, indicating that human skin is more susceptible to free radical formation and that a chromophore for visible light may be present. Using EPR spin-trapping techniques, UV radiation produced spin adducts consistent with trapping lipid alkyl radicals in mouse skin (α-[4-pyridyl 1-oxide]-N-tert-butyl nitrone/alkyl radical adduct; a N = 15.56 G and a H 2.70 G) and lipid alkoxyl radicals in human skin (5,5-dimethylpyrroline -1-oxide/alkoxyl radical adduct; a N = 14.54 G and a H = 16.0 G). Topical application of the iron chelator Desferal to human skin significantly decreases these radicals (∼50%), indicating a role for iron in lipid peroxidation. (Author)

Exceptionally High Protection of Photocarcinogenesis by Topical Application of (--Epi gal locatechin-3-Gal late in Hydrophilic Cream in SKH-1 Hairless Mouse Model: Relationship to Inhibition of UVB-Induced Global DNA Hypomethylation

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Anshu Mittal

2003-11-01

Full Text Available (--Epigallocatechin-3-gal late (EGCG has been shown to have potent antiphotocarcinogenic activity, but it was required to develop a cream-based formulation for topical application. For topical application, we tested hydrophilic cream as a vehicle for EGCG. Treatment with EGCG (≈ 1 mg/cm2 skin area in hydrophilic cream resulted in exceptionally high protection against photocarcinogenesis when determined in terms of tumor incidence, tumor multiplicity, and tumor size in a SKI-11-11 hairless mouse model. EGCG also inhibited malignant transformation of ultraviolet B (UVB-induced papillomas to carcinomas. In order to determine the mechanism of prevention of photocarcinogenesis, we determined the effect of EGCG on global DNA methylation pattern using monoclonal antibodies against 5-methyl cytosine and DNA methyltransferase in the long-term UV-irradiated skin because altered DNA methylation silencing is recognized as a molecular hallmark of human cancer. We found that treatment with EGCG resulted in significant inhibition of UVBinduced global DNA hypomethylation pattern. Longterm application of EGCG did not show any apparent sign of toxicity in mice when determined in terms of skin appearance, lean mass, total bone mineral content, and total bone mineral density but showed reduction in fat mass when analyzed using dual-energy X-ray absorptiometry. These data suggest that hydrophilic cream could be a suitable vehicle for topical application of EGCG, and that EGCG is a promising candidate for future cancer therapies based on its influence on the epigenetic pathway.

Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice

DEFF Research Database (Denmark)

Lerche, C.M.; Philipsen, P.A.; Poulsen, T.

2008-01-01

tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses...

Bathing Effects of Various Seawaters on Allergic (Atopic Dermatitis-Like Skin Lesions Induced by 2,4-Dinitrochlorobenzene in Hairless Mice

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Choong Gon Kim

2015-01-01

Full Text Available We evaluated the preventive effects of four types of seawater collected in Republic of Korea on hairless mice with 2,4-dinitrochlorobenzene- (DNCB- induced allergic/atopic dermatitis (AD. The anti-inflammatory effects were evaluated by measuring tumor necrosis factor- (TNF- α and interleukins (ILs. Glutathione (GSH, malondialdehyde (MDA, superoxide anion, and inducible nitric oxide synthase (iNOS were measured to evaluate the antioxidant effects. Caspase-3 and poly (ADP-ribose polymerase (PARP were observed to measure the antiapoptotic effects; matrix metalloproteinase- (MMP- 9 levels were also evaluated. Mice with AD had markedly higher clinical skin severity scores and scratching behaviors; higher TNF-α and ILs (1β, 10, 4, 5, and 13 levels; higher MDA, superoxide anion, caspase-3, PARP, and MMP-9 levels; and greater iNOS activity. However, the severity of AD was significantly decreased by bathing in seawaters, but it did not influence the dermal collagen depositions and skin tissue antioxidant defense systems. These results suggest that bathing in all four seawaters has protective effects against DNCB-induced AD through their favorable systemic and local immunomodulatory effects, active cytoprotective antiapoptotic effects, inhibitory effects of MMP activity and anti-inflammatory and antioxidative effects.

Garlic Supplementation Ameliorates UV-Induced Photoaging in Hairless Mice by Regulating Antioxidative Activity and MMPs Expression.

Science.gov (United States)

Kim, Hye Kyung

2016-01-08

UV exposure is associated with oxidative stress and is the primary factor in skin photoaging. UV-induced reactive oxygen species (ROS) cause the up-regulation of metalloproteinase (MMPs) and the degradation of dermal collagen and elastic fibers. Garlic and its components have been reported to exert antioxidative effects. The present study investigated the protective effect of garlic on UV-induced photoaging and MMPs regulation in hairless mice. Garlic was supplemented in the diet, and Skh-1 hairless mice were exposed to UV irradiation five days/week for eight weeks. Mice were divided into four groups; Non-UV, UV-irradiated control, UV+1% garlic powder diet group, and UV+2% garlic powder diet group. Chronic UV irradiation induced rough wrinkling of the skin with hyperkeratosis, and administration of garlic diminished the coarse wrinkle formation. UV-induced dorsal skin and epidermal thickness were also ameliorated by garlic supplementation. ROS generation, skin and serum malondialdehyde levels were significantly increased by UV exposure and were ameliorated by garlic administration although the effects were not dose-dependent. Antioxidant enzymes such as superoxide dismutase and catalase activities in skin tissues were markedly reduced by UV irradiation and garlic treatment increased these enzyme activities. UV-induced MMP-1 and MMP-2 protein levels were suppressed by garlic administration. Furthermore, garlic supplementation prevented the UV-induced increase of MMP-1 mRNA expression and the UV-induced decrease of procollagen mRNA expression. These results suggest that garlic may be effective for preventing skin photoaging accelerated by UV irradiation through the antioxidative system and MMP regulation.

RNA isolation for transcriptomics of human and mouse small skin biopsies

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Breit Timo M

2011-10-01

Full Text Available Abstract Background Isolation of RNA from skin biopsies presents a challenge, due to the tough nature of skin tissue and a high presence of RNases. As we lacked the dedicated equipment, i.e. homogenizer or bead-beater, needed for the available RNA from skin isolation methods, we adapted and tested our zebrafish single-embryo RNA-isolation protocol for RNA isolation from skin punch biopsies. Findings We tested our new RNA-isolation protocol in two experiments: a large-scale study with 97 human skin samples, and a small study with 16 mouse skin samples. Human skin was sampled with 4.0 mm biopsy punches and for the mouse skin different punch diameter sizes were tested; 1.0, 1.5, 2.0, and 2.5 mm. The average RNA yield in human samples was 1.5 μg with an average RNA quality RIN value of 8.1. For the mouse biopsies, the average RNA yield was 2.4 μg with an average RIN value of 7.5. For 96% of the human biopsies and 100% of the mouse biopsies we obtained enough high-quality RNA. The RNA samples were successfully tested in a transcriptomics analysis using the Affymetrix and Roche NimbleGen platforms. Conclusions Using our new RNA-isolation protocol, we were able to consistently isolate high-quality RNA, which is apt for further transcriptomics analysis. Furthermore, this method is already useable on biopsy material obtained with a punch diameter as small as 1.5 mm.

Role of Stat in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

International Nuclear Information System (INIS)

Macias, E.; Rao, D.; DiGiovanni, J.; DiGiovanni, J.; DiGiovanni, J.

2013-01-01

Signal transducer and activator of transcription 3 (Stat) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat-deficient mice have revealed that Stat plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat-deficient mouse models has demonstrated that Stat is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat in skin tumor progression. Studies using similar Stat-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat is an attractive target for skin cancer prevention and treatment.

Ultraviolet B radiation increases hairless mouse mast cells in a dose-dependent manner and alters distribution of UV-induced mast cell growth factor

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Kligman, L.H.; Murphy, G.F. [Pennsylvania Univ., Philadelphia, PA (United States). School of Medicine

1996-01-01

In studies of the effects of chronic UVB irradiation on dermal connective tissue in the hairless mouse, we observed that the number and size of mast cells was increased. Because mast cells are known to be associated with connective tissue remodeling, we examined and quantified the effect of increasing UVB (290-320 nm)doses on this cell. Groups of mice were exposed to filtered FS-40 Westinghouse lamps (290-400 nm: peak irradiance 313 nm) for 1-5 minimal erythema doses (MED) thrice weekly for 10 weeks. Appropriate controls were included. Biopsies, processed for light microscopy, were stained with toluidine blue. Mast cells were counted in 15 high-magnification fields per specimen with upper and lower dermis scored separately. Significant increases in large densely granular mast cells occurred at 2 MED in the lower dermic in association with the UVB-exacerbated granulomatous reaction. In the upper dermis, mast cells were significantly increased with 3 MED. These findings suggest that mast cells may play a dual role in UV-irradiated skin with those in the lower dermis related to inflammation processes and those in the upper dermis involved in connective tissue modeling. To gain understanding of the mechanism of mast cell recruitment and maturation, we examined the effect of UVB on mast cell growth factor expression. This was enhanced in the epidermis by UVB, with a shift from cytoplasmic staining to membrane-associated or intercellular staining at 2 MED and higher. Dermal dendritic and mononuclear cells also showed increased reactivity. (Author).

Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

International Nuclear Information System (INIS)

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

2013-01-01

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 +/− ) 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 +/− and Cx43 +/− 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 +/− 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

Oncogenic Radiation Abscopal Effects In Vivo: Interrogating Mouse Skin

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Mancuso, Mariateresa, E-mail: mariateresa.mancuso@enea.it [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Leonardi, Simona [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Giardullo, Paola; Pasquali, Emanuela [Department of Radiation Physics, Guglielmo Marconi University, Rome (Italy); Tanori, Mirella [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); De Stefano, Ilaria [Department of Radiation Physics, Guglielmo Marconi University, Rome (Italy); Casciati, Arianna [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy); Naus, Christian C. [Department of Cellular and Physiological Sciences, The Life Sciences Institute, University of British Columbia, Vancouver, British Columbia (Canada); Pazzaglia, Simonetta; Saran, Anna [Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l' Energia e lo Sviluppo Economico Sostenibile (ENEA), Casaccia Research Centre, Rome (Italy)

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.

Histochemical Localization of Glutathione Dependent NBT-Reductase in Mouse Skin

Institute of Scientific and Technical Information of China (English)

无

2001-01-01

Objective　Localization of the glutathione dependent Nitroblue tetrazolium (NBT) reductase in fresh frozen sections of mouse skin and possible dependence of NBT reductase on tissue thiol levels has been investigated. Methods　The fresh frozen tissue sections (8m thickness) were prepared and incubated in medium containing NBT, reduced glutathione (GSH) and phosphate buffer. The staining for GSH was performed with mercury orange. Results　 The activity of the NBT-reductase in mouse skin has been found to be localized in the areas rich in glutathione and actively proliferating area of the skin. Conclusion　The activity of the NBT-reductase seems to be dependent on the glutathione contents.

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

International Nuclear Information System (INIS)

Wohlman, Irene M.; Composto, Gabriella M.; Heck, Diane E.; Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D.; Casillas, Robert P.; Croutch, Claire R.; Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B.; Laskin, Jeffrey D.

2016-01-01

Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

Energy Technology Data Exchange (ETDEWEB)

Wohlman, Irene M.; Composto, Gabriella M. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Environmental Health Science, New York Medical College, Valhalla, NY (United States); Heindel, Ned D.; Lacey, C. Jeffrey; Guillon, Christophe D. [Department of Chemistry, Lehigh University, Bethlehem, PA (United States); Casillas, Robert P.; Croutch, Claire R. [MRIGlobal, Kansas City, MO (United States); Gerecke, Donald R.; Laskin, Debra L.; Joseph, Laurie B. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, NJ (United States)

2016-07-15

Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. - Highlights: • Sulfur mustard and nitrogen mustard are potent skin vesicants. • The endocannabinoid system regulates keratinocyte growth and differentiation. • Vesicants are potent inducers of the endocannabinoid system in mouse skin. • Endocannabinoid proteins upregulated are FAAH, CB1, CB2 and PPARα. • FAAH inhibitors suppress vesicant-induced inflammation in mouse skin.

X-rays and photocarcinogenesis in hairless mice.

Science.gov (United States)

Lerche, Catharina M; Philipsen, Peter A; Wulf, Hans Christian

2013-08-01

It is well known that excessive X-ray radiation can cause non-melanoma skin cancers. With the increased incidence of sun-related skin cancer there is a need to investigate the combination of sunlight and X-rays. Immunocompetent C3.Cg/TifBomTac mice (n = 298) were divided into 12 groups. Mice were irradiated with 12, 29 or 50 kV X-rays. The mice received a total dose of 45 Gy. They were irradiated with 3 SED simulated solar radiation (SSR) either before or after irradiation with X-rays. The groups irradiated with X-rays alone, 0, 3, 9 and 10 mice (0, 12, 29 and 50 kV, respectively) developed squamous cell carcinoma. In the groups irradiated with SSR after X-rays the development of tumours was significantly faster in the 50 kV group than in the corresponding control group (175 vs. 194 days, p X-ray radiation the development of tumours was significantly faster in the 29 and the 50 kV groups than in the corresponding control group (175 vs. 202 days, p X-ray radiation alone is a weak carcinogen in hairless mice. There is an added carcinogenic effect if X-ray radiation is given on prior sun-exposed skin or if the skin is sun-exposed after X-rays. We still believe that X-ray radiation is a safe and effective therapy for various dermatological diseases but caution should be observed if a patient has severely sun-damaged skin or has a high-risk sun behaviour.

Comparison of Moderate and High Energy of a Nano-Fractional Radiofrequency Treatment on a Photoaging Hairless Mice Model.

Science.gov (United States)

Sun, Wenjia; Zhang, Chengfeng; Zhao, Juemin; Wu, Jiaqiang; Xiang, Leihong

2018-04-01

Fractional radiofrequency (FRF) has been widely used in skin rejuvenation. To explore optimal settings, it is important to compare different treatment parameters. This study was designed to compare the effect of moderate-energy and high-energy FRF treatment on a hairless mice model. Fifteen photoaged hairless mice were assigned to 3 groups: control, moderate energy, and high energy. Two treatment sessions (T × 1 and T × 2) were performed at 1-month interval. Transepidermal water loss was measured at baseline, immediately, 1, 2, and 4 weeks after T × 1. Skin samples were harvested before each treatment, 1 and 2 months after T × 2. Neocollagenesis was evaluated by hematoxylin and eosin staining, Masson staining, and immunohistochemistry analysis. Transepidermal water loss of high-energy group was significantly higher than the moderate-energy group (p = .008) immediately after T × 1. Remarkable fibroblast proliferation was observed at 1 month after T × 1, followed by significant dermal thickening, and increase of Type I collagen and Type III collagen. There was no significant difference between 2 energy groups in fibroblast proliferation, dermal thickness, and collagen density. The effect of moderate-energy treatment was comparable with that of high energy in neocollagenesis, whereas moderate energy yielded less damage to skin barrier function.

Topical pimecrolimus and tacrolimus do not accelerate photocarcinogenesis in hairless mice after UVA or simulated solar radiation

DEFF Research Database (Denmark)

Lerche, C.M.; Philipsen, P.A.; Poulsen, T.

2009-01-01

in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done...

Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin

International Nuclear Information System (INIS)

Divya, Sasidharan Padmaja; Wang, Xin; Pratheeshkumar, Poyil; Son, Young-Ok; Roy, Ram Vinod; Kim, Donghern; Dai, Jin; Hitron, John Andrew; Wang, Lei; Asha, Padmaja; Shi, Xianglin; Zhang, Zhuo

2015-01-01

Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm 2 ) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E 2 (PGE 2 ), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways. - Highlights: • Blackberry extract inhibits UVB-induced glutathione depletion. • Blackberry

Blackberry extract inhibits UVB-induced oxidative damage and inflammation through MAP kinases and NF-κB signaling pathways in SKH-1 mice skin

Energy Technology Data Exchange (ETDEWEB)

Divya, Sasidharan Padmaja; Wang, Xin; Pratheeshkumar, Poyil; Son, Young-Ok; Roy, Ram Vinod [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern; Dai, Jin [Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Asha, Padmaja [National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin (India); Shi, Xianglin [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Zhang, Zhuo, E-mail: zhuo.zhang@uky.edu [Department of Toxicology and Cancer Biology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

2015-04-01

Extensive exposure of solar ultraviolet-B (UVB) radiation to skin induces oxidative stress and inflammation that play a crucial role in the induction of skin cancer. Photochemoprevention with natural products represents a simple but very effective strategy for the management of cutaneous neoplasia. In this study, we investigated whether blackberry extract (BBE) reduces chronic inflammatory responses induced by UVB irradiation in SKH-1 hairless mice skin. Mice were exposed to UVB radiation (100 mJ/cm{sup 2}) on alternate days for 10 weeks, and BBE (10% and 20%) was applied topically a day before UVB exposure. Our results show that BBE suppressed UVB-induced hyperplasia and reduced infiltration of inflammatory cells in the SKH-1 hairless mice skin. BBE treatment reduced glutathione (GSH) depletion, lipid peroxidation (LPO), and myeloperoxidase (MPO) in mouse skin by chronic UVB exposure. BBE significantly decreased the level of pro-inflammatory cytokines IL-6 and TNF-α in UVB-exposed skin. Likewise, UVB-induced inflammatory responses were diminished by BBE as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, BBE also reduced inflammatory mediators such as cyclooxygenase-2 (COX-2), prostaglandin E{sub 2} (PGE{sub 2}), and inducible nitric oxide synthase (iNOS) levels in UVB-exposed skin. Treatment with BBE inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mouse skin. Immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG), cyclobutane pyrimidine dimers (CPD), proliferating cell nuclear antigen (PCNA), and cyclin D1 in UVB-exposed skin. Collectively, these data indicate that BBE protects from UVB-induced oxidative damage and inflammation by modulating MAP kinase and NF-κB signaling pathways. - Highlights: • Blackberry extract inhibits UVB-induced glutathione depletion. �

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

International Nuclear Information System (INIS)

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, 14 C-BaP was incubated with 3-methylcholanthrene (3-MC) induced C 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 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

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

Energy Technology Data Exchange (ETDEWEB)

Xia, Xiaojun [The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Park, Eunmi [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Fischer, Susan M. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78967 (United States); Hu, Yinling, E-mail: huy2@mail.nih.gov [Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701 (United States)

2013-02-15

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.

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

International Nuclear Information System (INIS)

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

The circadian clock controls sunburn apoptosis and erythema in mouse skin.

Science.gov (United States)

Gaddameedhi, Shobhan; Selby, Christopher P; Kemp, Michael G; Ye, Rui; Sancar, Aziz

2015-04-01

Epidemiological studies of humans and experimental studies with mouse models suggest that sunburn resulting from exposure to excessive UV light and damage to DNA confers an increased risk for melanoma and non-melanoma skin cancer. Previous reports have shown that both nucleotide excision repair, which is the sole pathway in humans for removing UV photoproducts, and DNA replication are regulated by the circadian clock in mouse skin. Furthermore, the timing of UV exposure during the circadian cycle has been shown to affect skin carcinogenesis in mice. Because sunburn and skin cancer are causally related, we investigated UV-induced sunburn apoptosis and erythema in mouse skin as a function of circadian time. Interestingly, we observed that sunburn apoptosis, inflammatory cytokine induction, and erythema were maximal following an acute early-morning exposure to UV and minimal following an afternoon exposure. Early-morning exposure to UV also produced maximal activation of ataxia telangiectasia mutated and Rad3-related (Atr)-mediated DNA damage checkpoint signaling, including activation of the tumor suppressor p53, which is known to control the process of sunburn apoptosis. These data provide early evidence that the circadian clock has an important role in the erythemal response in UV-irradiated skin. The early morning is when DNA repair is at a minimum, and thus the acute responses likely are associated with unrepaired DNA damage. The prior report that mice are more susceptible to skin cancer induction following chronic irradiation in the AM, when p53 levels are maximally induced, is discussed in terms of the mutational inactivation of p53 during chronic irradiation.

The co-application effects of fullerene and ascorbic acid on UV-B irradiated mouse skin

International Nuclear Information System (INIS)

Ito, Shinobu; Itoga, Kazuyoshi; Yamato, Masayuki; Akamatsu, Hirohiko; Okano, Teruo

2010-01-01

The role of fullerene as a pro-oxidant or anti-oxidant in Ultraviolet B ray (UV-B)-induced disorders in mouse skin was investigated. Fullerene gave no photo-toxic effect to UV-B-irradiated mouse skin. Since erythema was concentrated at the pore circumference in a UV-B irradiation experiment in mouse skin, the sebaceous gland pairs was strongly implicated as a site for the generation of reactive oxygen species (ROS). In a histological evaluation of the skin stained with CH 3 MDFDA (ROS index) and YO-Pro-1 (apoptosis index), the fluorescence intensity of a sebaceous gland significantly increased with UV-B irradiation. With the application of fullerene to UV-irradiated mouse skin, no toxicity was recognized in comparison with the control, and erythema, the ROS index, and the apoptosis index decrease with the application of fullerene. Ascorbyl radical (AA·) increased with the application of ascorbate (AA) to UV-B-irradiated mouse skin, and AA· decreased with the application of fullerene. The co-application of AA and fullerene, which suppressed AA· in vitro, significantly suppressed erythema, and also suppressed both the ROS index and apoptosis index in mouse skin after UV-B irradiation. In both mouse skin at 48 h after UV-B irradiation and in an attempt to reproduce this phenomenon artificially in vitro, a similar high AA· peak (AA·/H· > 4) was observed in electron spin resonance (ESR) charts. The binding of fullerene with AA impairs the Fenton reaction between AA and Fe-protein based on the observation of ascorbate-specific UV absorption and a linear equation for the calibration curve. Therefore, fullerene may impair the intercalation of AA to a heme pocket by binding with AA. These results suggest that the co-application of AA and fullerene is effective against oxidative skin damage caused by UV-B irradiation, and the development of an AA· inhibitor such as fullerene should be useful for reducing organ damage associated with Fe-protein oxidation.

Effect of Bifidobacterium breve B-3 on skin photoaging induced by chronic UV irradiation in mice.

Science.gov (United States)

Satoh, T; Murata, M; Iwabuchi, N; Odamaki, T; Wakabayashi, H; Yamauchi, K; Abe, F; Xiao, J Z

2015-01-01

Probiotics have been shown to have a preventative effect on skin photoaging induced by short term UV irradiation, however, the underlying mechanisms and the effect of probiotics on skin photoaging induced by chronic UV irradiation remain unclear. In this study, we investigated the effect of Bifidobacterium breve B-3 on skin photoaging induced by chronic UV irradiation in hairless mice. Mice were irradiated with UVB three times weekly and orally administered B. breve B-3 (2×10(9) cfu/mouse /day) for 7 weeks. Nonirradiated mice and UVB-irradiated mice without probiotic treatment were used as controls. B. breve B-3 significantly suppressed the changes of transepidermal water loss, skin hydration, epidermal thickening and attenuated the damage to the tight junction structure and basement membrane induced by chronic UVB irradiation. Administration of B. breve B-3 tended to suppress the UV-induced interleukin-1β production in skin (P=0.09). These results suggest that B. breve B-3 could potentially be used to prevent photoaging induced by chronic UV irradiation.

Red tattoos, ultraviolet radiation and skin cancer in mice

DEFF Research Database (Denmark)

Lerche, Catharina M.; Heerfordt, Ida M.; Serup, Jørgen

2017-01-01

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were...

Radiosensitization of mouse skin by oxygen and depletion of glutathione

International Nuclear Information System (INIS)

Stevens, Graham; Joiner, Michael; Joiner, Barbara; Johns, Helen; Denekamp, Juliana

1995-01-01

Purpose: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Methods and Materials: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O 2 . The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O 2 . Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of dl-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. Results: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O 2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O 2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH

Cutaneous injury-related structural changes and their progression following topical nitrogen mustard exposure in hairless and haired mice.

Directory of Open Access Journals (Sweden)

Neera Tewari-Singh

Full Text Available To identify effective therapies against sulfur mustard (SM-induced skin injuries, various animals have been used to assess the cutaneous pathology and related histopathological changes of SM injuries. However, these efforts to establish relevant skin injury endpoints for efficacy studies have been limited mainly due to the restricted assess of SM. Therefore, we employed the SM analog nitrogen mustard (NM, a primary vesicating and bifunctional alkylating agent, to establish relevant endpoints for efficient efficacy studies. Our published studies show that NM (3.2 mg exposure for 12-120 h in both the hairless SKH-1 and haired C57BL/6 mice caused clinical sequelae of toxicity similar to SM exposure in humans. The NM-induced cutaneous pathology-related structural changes were further analyzed in this study and quantified morphometrically (as percent length or area of epidermis or dermis of skin sections in mice showing these lesions. H&E stained skin sections of both hairless and haired mice showed that NM (12-120 h exposure caused epidermal histopathological effects such as increased epidermal thickness, epidermal-dermal separation, necrotic/dead epidermis, epidermal denuding, scab formation, parakeratosis (24-120 h, hyperkeratosis (12-120 h, and acanthosis with hyperplasia (72-120 h. Similar NM exposure in both mice caused dermal changes including necrosis, edema, increase in inflammatory cells, and red blood cell extravasation. These NM-induced cutaneous histopathological features are comparable to the reported lesions from SM exposure in humans and animal models. This study advocates the usefulness of these histopathological parameters observed due to NM exposure in screening and optimization of rescue therapies against NM and SM skin injuries.

The hairless guinea-pig as a model for treatment of acute irritation in humans

DEFF Research Database (Denmark)

Andersen, F; Hedegaard, K; Fullerton, A

2006-01-01

BACKGROUND: The effect of six skin care formulations on experimentally induced acute irritation was studied in hairless guinea-pigs (HLGP) and in human volunteers (HV). The formulations were a basic cream, a carbomer cream and four modifications of the carbomer cream, containing either 10...... and colorimetry. RESULTS: The glycerol cream was the only product showing effects potentially better than no treatment in HV. CONCLUSION: The HLGP was too sensitive an animal model as a predictor for effect in humans. There was no difference in efficacy of the formulations against the two different irritants...

Temperature Preference in IAF Hairless and Hartley Guinea Pigs (Cavia porcellus).

Science.gov (United States)

Kleven, Gale A; Joshi, Prianca

2016-03-01

The Hairless strain of guinea pigs (Cavia porcellus) is the result of a spontaneous recessive mutation first identified at the Institute Armand Frappier (IAF) in 1978. Despite the longstanding availability of this strain, little is known about its thermoregulatory behavior. The aim of this study was to determine temperature preference in Hartley and Hairless guinea pigs by observing each strain in a ring-shaped apparatus containing a nonlinear temperature gradient. Temperatures were maintained by separately controlled heating mats lining the apparatus. Set point temperatures ranged from 24 to 38 °C. Guinea pigs (Hartley female, Hairless female, and Hairless male guinea pigs; n = 8 each group) were placed either singly or in pairs at 1 of the 8 randomized starting points within the apparatus. Subjects were observed for 30 min and coded for location within the temperature gradient by both frequency and duration. When placed singly in the apparatus, all 3 groups spent more time in the 30 °C zones. However, when placed as pairs with a cagemate, Hartley female guinea pigs spent more time in the cooler range of temperatures from 24 to 30 °C, whereas Hairless guinea pigs preferred a range of 30 to 38 °C. These results confirm a temperature preference of 30 ± 2 °C for both Hartley and Hairless guinea pigs when singly housed. However, data from the paired housing condition suggest that context plays an important role in thermoregulatory behavior.

Effect of Enhancers on in vitro and in vivo Skin Permeation and Deposition of S-Methyl-L-Methionine.

Science.gov (United States)

Kim, Ki Taek; Kim, Ji Su; Kim, Min-Hwan; Park, Ju-Hwan; Lee, Jae-Young; Lee, WooIn; Min, Kyung Kuk; Song, Min Gyu; Choi, Choon-Young; Kim, Won-Serk; Oh, Hee Kyung; Kim, Dae-Duk

2017-07-01

S-methyl- L -methionine (SMM), also known as vitamin U, is commercially available as skin care cosmetic products for its wound healing and photoprotective effects. However, the low skin permeation expected of SMM due to its hydrophilic nature with a log P value of -3.3, has not been thoroughly addressed. The purpose of this study thus was to evaluate the effect of skin permeation enhancers on the skin permeation/deposition of SMM. Among the enhancers tested for the in vitro skin permeation and deposition of SMM, oleic acid showed the most significant enhancing effect. Moreover, the combination of oleic acid and ethanol further enhanced in vitro permeation and deposition of SMM through hairless mouse skin. Furthermore, the combination of oleic acid and ethanol significantly increased the in vivo deposition of SMM in the epidermis/dermis for 12 hr, which was high enough to exert a therapeutic effect. Therefore, based on the in vitro and in vivo studies, the combination of oleic acid and ethanol was shown to be effective in improving the topical skin delivery of SMM, which may be applied in the cosmetic production process for SMM.

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

Science.gov (United States)

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

Studies on the production and utilization of radioisotopes - Treatment of= skin cancer with Ho-166 skin patch in an animal model

Energy Technology Data Exchange (ETDEWEB)

Kim, Jae Rok [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Lee, Jong Doo [Yonsei University, Seoul (Korea, Republic of)

1995-07-01

Skin cancers were developed in 8 ICR mice and 2 hairless mice by topical application of chemical compound (TDA and NPO) for 35 wks. Specially designed= Ho-166 skin patches were applied over the skin cancer for 1-2 hrs to deliver 8000 rads to the tumors. Complete, destruction of tumors as well as regeneration of epithelium were observed after the treatment. In conclusion, Ho-166 patch is a useful treatment modality in superficial skin cancers. 10 refs., 4 tabs., 4 figs. (author)

Unscheduled DNA synthesis after β-irradiation of mouse skin in situ

International Nuclear Information System (INIS)

Ootsuyama, Akira; Tanooka, Hiroshi

1986-01-01

The skin of ICR mouse was irradiated with β-rays from 90 Sr- 90 Y with surface doses up to 30 krad. Unscheduled DNA synthesis (UDS) was measured by autoradiography after labeling the skin with radioactive thymidine using the forceps-clamping method. The level of UDS in epithelial cells of the skin was detected as an increasing function of radiation dose. Fibroblastic cells, compared with epithelial cells and hair follicle cells at the same depth of the skin, showed a lower level of UDS, indicating a lower DNA repair activity in fibroblasts. Cancer risk of the skin was discussed. (Auth.)

Effect of synthetic vernix biofilms on barrier recovery of damaged mouse skin

NARCIS (Netherlands)

Oudshoorn, M.H.M.; Rissmann, R.; van der Coelen, D.; Hennink, W.E.; Ponec, M.; Bouwstra, J.A.

2009-01-01

The aim of this work was to investigate whether topical application of synthetic biofilms supports and accelerates the recovery of the murine skin barrier, disrupted by sequential tape stripping. Therefore, various biofilms were applied topically on disrupted mouse skin to determine which

Chronic ionizing radiation exposure as a tumor promoter in mouse skin

International Nuclear Information System (INIS)

Mitchel, R.E.J.; Trivedi, A.

1992-01-01

We have tested a chronic exposure to 90 Y beta-radiation as a tumor promoter in mouse skin previously exposed to a chemical tumor initiator. Three different tests of radiation as a stage I tumor promoter, in skin subsequently given chemical stage II promotion, all indicated that the beta-radiation acted as a weak stage I skin tumor promoter. It showed no action as either a stage II or complete tumor promoter. (author)

Improved penetration of wild ginseng extracts into the skin using low-temperature atmospheric pressure plasma

Science.gov (United States)

Nam, Seoul Hee; Hae Choi, Jeong; Song, Yeon Suk; Lee, Hae-June; Hong, Jin-Woo; Kim, Gyoo Cheon

2018-04-01

Wild ginseng (WG) is a well-known traditional medicinal plant that grows in natural environments in deep mountains. WG has been thought to exert potent physiological and medicinal effects, and, recently, its use in skin care has attracted much interest. This study investigated the efficient penetration of WG extracts into the skin by means of low-temperature atmospheric pressure plasma (LTAPP), and its effects on the skin at the cellular and tissue levels. NIH3T3 mouse embryonic fibroblasts and HRM-2 hairless mice were used to confirm the improved absorption of WG extracts into the skin using LTAPP. The gene expression levels in NIH3T3 cells and morphological changes in skin tissues after WG treatment were monitored using both in vitro and in vivo experiments. Although WG extracts did not show any significant effects on proliferative activity and cytotoxicity, at a concentration of 1:800, it significantly increased the expression of fibronectin and vascular endothelial growth factor. In the in vivo study, the combinational treatment of LTAPP and WG markedly induced the expression of fibronectin and integrin α6, and it thickened. Our results showed that LTAPP treatment safely and effectively accelerated the penetration of the WG extracts into the skin, thereby increasing the effects of WG on the skin.

Silibinin attenuates sulfur mustard analog-induced skin injury by targeting multiple pathways connecting oxidative stress and inflammation.

Directory of Open Access Journals (Sweden)

Neera Tewari-Singh

Full Text Available Chemical warfare agent sulfur mustard (HD inflicts delayed blistering and incapacitating skin injuries. To identify effective countermeasures against HD-induced skin injuries, efficacy studies were carried out employing HD analog 2-chloroethyl ethyl sulfide (CEES-induced injury biomarkers in skin cells and SKH-1 hairless mouse skin. The data demonstrate strong therapeutic efficacy of silibinin, a natural flavanone, in attenuating CEES-induced skin injury and oxidative stress. In skin cells, silibinin (10 µM treatment 30 min after 0.35/0.5 mM CEES exposure caused a significant (p90%, and activation of transcription factors NF-κB and AP-1 (complete reversal. Similarly, silibinin treatment was also effective in attenuating CEES-induced oxidative stress measured by 4-hydroxynonenal and 5,5-dimethyl-2-(8-octanoic acid-1-pyrolline N-oxide protein adduct formation, and 8-oxo-2-deoxyguanosine levels. Since our previous studies implicated oxidative stress, in part, in CEES-induced toxic responses, the reversal of CEES-induced oxidative stress and other toxic effects by silibinin in this study indicate its pleiotropic therapeutic efficacy. Together, these findings support further optimization of silibinin in HD skin toxicity model to develop a novel effective therapy for skin injuries by vesicants.

Development of Protective Agent Against Sulfur Mustard-Induced Skin Lesions

National Research Council Canada - National Science Library

Wormser, Uri

2001-01-01

.... Toxicokinetic studies with male, fur-covered and hairless guinea pigs showed that SM disappeared from the skin 60 min after exposure whereas in the female, fur-covered guinea pig SM disappeared after 3 hours...

Evaluation of the Photoprotective Effect of Dongchongxiacao (Paecilomyces japonica) Extract against Ultraviolet Radiation-induced Skin Wrinkling and Cancer

International Nuclear Information System (INIS)

Lee, Hae June; Moon, Chang Jong; Kim, Jong Choon; Kim Sung Ho; Jung, Uhee; Jo, Sung Kee; Jang, Jong Sik

2012-01-01

To evaluate the ability of Dongchongxiacao (Paecilomyces japonica ) extract (PJE) to protect the skin from photo damage, the gross and microscopic changes in the skin of hairless mice and PJE-treated mice exposed chronically to ultraviolet (UV) were examined. The skin of the UV-irradiated mice showed characteristic signs of photo aging, such as deep wrinkles across the back. PJE-treated mice showed a significantly decreased wrinkling score. By the 22nd week, 88.9% (i.p. with saline) or 44.4% (topical administration with cream base) of the UV-irradiated mice developed at least one tumor. PJE delayed tumor onset significantly. PJE (i.p.) was also effective in reducing the occurrence of UV radiation-induced skin tumors and reduced the number of tumors per mouse. After 22 weeks of treatment, 80.0% (i.p.) and 75.0% (topical) of the mice treated with PJE were tumor-free. Tumor multiplicity was reduced by 96.2% (i.p.) in the PJE treated groups. It is noted that skin that is chronically exposed to UV is subject to photo aging and photo carcinogenesis and regular use of PJE would prevent these photo damaging effects of UV.

Studying skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice using chronic 7,12-dimethylbenz(a)anthracene topical applications to develop a useful experimental skin cancer model

NARCIS (Netherlands)

Thomas, Giju; Tuk, Bastiaan; Song, Ji-Ying; Truong, Hoa; Gerritsen, Hans C.; de Gruijl, Frank R.; Sterenborg, Henricus J. C. M.

2017-01-01

Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumourigenesis in conventional furred mouse models by acting on hair follicle stem cells. However, further cancer progression depends on repeated applications of tumour promoter agents. This study

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

International Nuclear Information System (INIS)

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

2007-01-01

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

In-vivo data on the influence of tobacco smoke and UV light on murine skin.

Science.gov (United States)

Pavlou, P; Rallis, M; Deliconstantinos, G; Papaioannou, G; Grando, S A

2009-01-01

Inhaled tobacco smoke comes in direct contact with few organs such as mouth, lungs, and stomach. Cigarette smoke (CS) in lungs has been extensively studied. However, limited data exist on its effect on skin, and there are no long-term experimental studies suggesting toxic effects on skin. Even though it is generally accepted that CS is among the main factors of skin aging, the number of experimental studies showing this aging effect is limited. We hereby studied the effect of long-term exposure to CS on the skin of hairless mice in combination with or without ultraviolet (UV) light. In addition, we investigated potential skin protection by a potent antioxidant namely procyanidine-rich French maritime pine bark extract (PBE) pycnogenol. Male and female hairless SKH-2 mice were exposed for 10 months to tobacco smoke and/or UV light in vivo, and their effects on skin were investigated. Some biophysical parameters such as development of erythema, transepidermal water loss (TEWL), and skin elasticity were measured. The results show that UV and CS may be acting synergistically, as shown by the enhanced TEWL, erythema values, epitheliomas, and squamous cell carcinomas (SCCs) observed, whereas PBE seems to protect skin against SCC.

Changes in the radiation sensitivity of mouse skin during fractionated and prolonged treatments

International Nuclear Information System (INIS)

Ruifrok, A.C.C.; Mason, K.A.; Hunter, N.; Thames, H.D.

1994-01-01

Reactions of the skin of the right thigh of mice were used as an experimental model to test possible changes in the radiosensitivity of mouse skin, as represented by changes in the linear-quadratic (LQ) model parameters α and β, as a function of fractionation interval and overall treatment time. In the first series of experiments, variable numbers of 3-Gy fractions with intervals of 6, 24 or 48 h were applied, followed by top-up doses to increase the skin damage to a level that could be scored. The results showed that mouse skin is more sensitive to 3-Gy fractions applied with 48-h intervals than to 3-Gy fractions applied with 6- or 24-h intervals. In the second series of experiments we used single-dose or fractonated test treatments for previously unirradiated mice and mice treated with priming doses of 10, 20 or 30 Gy given 1-18 days before the test treatment. The sensitivity appeared to be higher after intervals of 14-18 days than after 1-10 days after priming treatments of 20 and 30 Gy. The increased sensitivity 18 days after 20 Gy was mainly the result of an increase in the β component of the LQ model; higher values of α were also determined. We conclude that the radiosensitivity of mouse skin is higher during a radiation-induced proliferative response. 28 refs., 3 figs., 7 tabs

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

Directory of Open Access Journals (Sweden)

Kumar A

2011-06-01

Full Text Available Amit Kumar, Xinran Li, Michael A Sandoval, B Leticia Rodriguez, Brian R Sloat, Zhengrong CuiUniversity of Texas at Austin, College of Pharmacy, Pharmaceutics Division, Austin, TX, USABackground: 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.Keywords: antibody responses, safety of microneedles, transepidermal water loss

Is Lack of Sleep Capable of Inducing DNA Damage in Aged Skin?

OpenAIRE

Kahan, Vanessa [UNIFESP; Ribeiro, Daniel Araki [UNIFESP; Egydio, Flavia [UNIFESP; Barros, L. A. [UNIFESP; Tomimori, Jane [UNIFESP; Tufik, Sergio [UNIFESP; Andersen, Monica Levy [UNIFESP

2014-01-01

Skin naturally changes with age, becoming more fragile. Various stimuli can alter skin integrity. the aim of this study was to evaluate whether sleep deprivation affects the integrity of DNA in skin and exacerbates the effects of aging. Fifteen-month old female Hairless mice underwent 72 h of paradoxical sleep deprivation or 15 days of chronic sleep restriction. Punch biopsies of the skin were taken to evaluate DNA damage by single cell gel (comet) assay. Neither paradoxical sleep deprivation...

UV light B-mediated inhibition of skin catalase activity promotes Gr-1+ CD11b+ myeloid cell expansion.

Science.gov (United States)

Sullivan, Nicholas J; Tober, Kathleen L; Burns, Erin M; Schick, Jonathan S; Riggenbach, Judith A; Mace, Thomas A; Bill, Matthew A; Young, Gregory S; Oberyszyn, Tatiana M; Lesinski, Gregory B

2012-03-01

Skin cancer incidence and mortality are higher in men compared with women, but the causes of this sex discrepancy remain largely unknown. UV light exposure induces cutaneous inflammation and neutralizes cutaneous antioxidants. Gr-1(+)CD11b(+) myeloid cells are heterogeneous bone marrow-derived cells that promote inflammation-associated carcinogenesis. Reduced activity of catalase, an antioxidant present in the skin, has been associated with skin carcinogenesis. We used the outbred, immune-competent Skh-1 hairless mouse model of UVB-induced inflammation and non-melanoma skin cancer to further define sex discrepancies in UVB-induced inflammation. Our results demonstrated that male skin had relatively lower baseline catalase activity, which was inhibited following acute UVB exposure in both sexes. Further analysis revealed that skin catalase activity inversely correlated with splenic Gr-1(+)CD11b(+) myeloid cell percentage. Acute UVB exposure induced Gr-1(+)CD11b(+) myeloid cell skin infiltration, which was inhibited to a greater extent in male mice by topical catalase treatment. In chronic UVB studies, we demonstrated that the percentage of splenic Gr-1(+)CD11b(+) myeloid cells was 55% higher in male tumor-bearing mice compared with their female counterparts. Together, our findings indicate that lower skin catalase activity in male mice may at least in part contribute to increased UVB-induced generation of Gr-1(+)CD11b(+) myeloid cells and subsequent skin carcinogenesis.

Protective effect of (-)-epigallocatechin gallate on ultraviolet b ...

African Journals Online (AJOL)

... EGCg shows dose-dependent protective effect against UV-B-induced damage on hairless mouse skin. Thus, the plant compound can potentially be used as an alternative agent for photoprotection against UV-B exposure. Keywords: UV-B, Green tea EGCg, Photoprotection, Stratum corneum, Mitochondrion, Melanosome ...

Human atopic dermatitis skin-derived T cells can induce a reaction in mouse keratinocytes in vivo

DEFF Research Database (Denmark)

Martel, Britta C; Blom, Lars; Dyring-Andersen, Beatrice

2015-01-01

. In comparison, blood -derived in vitro differentiated Th2 cells only induced a weak response in a few of the mice. Thus, we conclude that human AD skin-derived T cells can induce a reaction in mouse skin through induction of a proliferative response in the mouse keratinocytes. This article is protected......In atopic dermatitis (AD), the inflammatory response between skin infiltrating T cells and keratinocytes is fundamental to the development of chronic lesional eczema. The aim of this study was to investigate whether skin-derived T cells from AD patients could induce an inflammatory response in mice...... through keratinocyte activation and consequently cause development of eczematous lesions. Punch biopsies of lesional skin from AD patients were used to establish skin-derived T cell cultures and which were transferred into NOD.Cg-Prkd(scid) Il2rg(tm1Sug) /JicTac (NOG) mice. We found that subcutaneous...

Use of mouse thigh as a radiobiological model of radiation-induced skin reactions

International Nuclear Information System (INIS)

Smith, A.J.; Hagkyriakou, H.; Martin, R.F.

2000-01-01

Full text: The effects of radiation exposure on skin have been widely studied. One of the most useful and relatively easy methods for evaluating radiation-induced skin reactions is the mouse thigh model. This model is non-invasive and has the advantage of not requiring the use of anaesthetic. In the current adaptation of the mouse thigh model, female C3H/HeJ ARC mice (from the Animal Resource Centre, W.A.) were used. The mice were restrained in specially designed jigs where the right leg was held in place by a metal hook. Lead shielding ensured that only the right ventral thigh was exposed to the radiation beam. A 6MeV electron beam from a Varian 2100 Linac (20Gy / minute) was used, thus minimising the time for which the mice were restrained. Eight to twelve days after exposure to the radiation, the first skin reactions can be seen. These are scored according to a scale ranging from 0 (no visible reaction) to 3.5 (breakdown of the entire area with severe exudation). The skin reactions (erythema and moist desquamation) peak approximately 18-22 days after radiation exposure and may remain at peak for only 1-3 days. Therefore, the reactions need to be scored daily and this continues, generally until day 35, or until all moist desquamation has healed. The maximum score in a score versus time profile for each mouse in a group of 5-6 animals are averaged. Radiation-dose response data will be presented. Using the mouse thigh model, hair loss can also be measured (usually on about day 30-35) using a scale from 0-4, where 0 depicts no evident hair loss and 4 represents complete epilation. Leg contraction can also be measured as a late effect by comparison with the length of the unirradiated leg

Light fractionation increases the efficacy of ALA-PDT but not of MAL-PDT: What is the role of (vascular) endothelial cells?

Science.gov (United States)

de Bruijn, H. S.; de Vijlder, H. C.; de Haas, E. R. M.; van der Ploeg-van den Heuvel, A.; Kruijt, B.; Poel-Dirks, D.; Sterenborg, H. J. C. M.; ten Hagen, T. L. M.; Robinson, D. J.

2009-06-01

Photodynamic therapy (PDT) using protoporpyrin IX (PpIX) precursors like 5-aminolevulinic acid (ALA) or methyl-aminolevulinate (MAL) has shown to be effective in the treatment of various skin diseases. Using ALA we have shown in numerous studies a significantly improved efficacy by applying light fractionation with a long dark interval. In contrast, in the hairless mouse model, the PDT efficacy using MAL is unaffected by adopting this approach. More acute edema is found after ALA-PDT suggesting a difference in response of endothelial cells to PDT. To investigate the role of endothelial cells, cryo-sections of hairless mouse skin after 4 hours of topical MAL or ALA application were stained with a fluorescent endothelial cell marker (CD31). Co-localization of this marker with the PpIX fluorescence was performed using the spectral imaging function of the confocal microscope. We have also used intra-vital confocal microscopy to image the PpIX fluorescence distribution in correlation with the vasculature of live mouse skin. Our results show PpIX fluorescence at depth in cryo-sections of mouse skin after 4 hours of topical application. Co-localization has shown to be difficult due to the changes in tissue organization caused by the staining procedure. As expected we found high PpIX fluorescence levels in the epidermis after both MAL and ALA application using intra-vital microscopy. After ALA application more PpIX fluorescence was found deep in the dermal layer of the skin than after MAL. Furthermore we detected localized fluorescence in unidentified structures that could not be correlated to blood vessels or nerves.

Absence of photoreactivation of pyrimidine dimers in the epidermis of hairless mice following exposures to ultraviolet light

Energy Technology Data Exchange (ETDEWEB)

Ley, R D; Sedita, B A; Grube, D D

1978-01-01

The influence of photoreactivating light on the fate of uv-induced DNA damage has been measured in the epidermis of hairless mice using damage-specific endonuclease from Micrococcus luteus. Groups of mice were exposed to varying fluences of uv at 297 nm or from an FS40 fluorescent sun lamp to induce uv photoproducts. The same fluence-dependent DNA damage was observed in high molecular weight epidermal DNA regardless of whether the mice were killed immediately, or maintained in the dark or under photorectivating light for 20 h after uv. Thus, no detectable photoreactivation of uv-induced pyrimidine dimers could be demonstrated in mouse epithelial cells in vivo.

The potential of the essential fatty acid-deficient hairless rat as a psoriasis screening model for topical anti-proliferative drugs

DEFF Research Database (Denmark)

Jensen, Mette; Groth, L.; Holmer, G.

2002-01-01

were fed with a fat-free diet lacking linoleic acid. The EFAD condition was established within 8 weeks. In order to ensure that this condition had been established, several parameters were measured and observed, i.e. animal weight, water consumption, transepidermal water loss, clinical skin symptoms...... with calcipotriol. Dithranol and its coal tar-containing vehicle also showed a reductive effect on epidermal thickness. EFAD hairless rats possess various histological changes resembling psoriasis. These histological changes normalise during treatment with anti-psoriatic drugs as calcipotriol, dithranol and coal...

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

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Ganesh Chandra Jagetia

2015-01-01

Full Text Available 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.

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

Science.gov (United States)

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

2016-09-01

Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Barrier abnormalities and keratinocyte-derived cytokine cascade after cessation of long-term topical glucocorticosteroid on hairless mouse skin

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Tzu-Kai Lin

2015-06-01

Conclusion: An epidermis-derived cytokine cascade was observed following TCS-induced barrier disruption, which is similar to that from permeability barrier insults by acetone or tape stripping. The study suggests that concurrent application of skin care products during TCS treatment improves barrier homeostasis, and should become a standard practice to alleviate TCS-induced WD.

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

International Nuclear Information System (INIS)

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

1997-01-01

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 → A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C → T, two C → A, one C → G, and one A → 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

The acute effects of different energy beta-emitters on pig and mouse skin

International Nuclear Information System (INIS)

Hopewell, J.W.; Hamlet, R.; Wells, J.; Charles, M.W.

1986-01-01

Acute changes were studied in the skin of mice and pigs following irradiation with Sr 90 (Esub(max) 2.27 MeV), Tm 170 (Esub(max) 0.97 MeV) and Pm 147 (Esub(max) 0.225 MeV). Sr 90 irradiation in the pig and Sr 90 and Tm 170 exposure in the mouse resulted in a distinct field-size effect for sources of 5-22.5 mm diameter; ED 50 values for moist desquamation were 22.0-27.5 Gy from the 22.5 mm source and 75-90 Gy for the 5 mm source. Tm 170 irradiation in the pig produced no distinct area effect for sources of 5-19 mm diameter (ED 50 approx.= 80 Gy). Acute tissue breakdown was only achieved in pig and mouse skin by very high doses (ED 50 >= 140 Gy) from sources of 147 produced acute epithelial breakdown, only after high skin-surface doses (ED 50 550-725 Gy). Area-and energy-related changes can, in part be explained by an hypothesis based on repopulation of the epithelium in the irradiated area by the migration of either cells from the edge of that area and/or cells surviving at the base of hair follicles. Differences in the results in pig and mouse can be explained on the basis of the distribution of target cells in the epidermis at varying depths. (author)

Analysis of a Mouse Skin Model of Tuberous Sclerosis Complex.

Directory of Open Access Journals (Sweden)

Yanan Guo

Full Text Available 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.

Xenobiotic-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Science.gov (United States)

Oesch, F; Fabian, E; Guth, K; Landsiedel, R

2014-12-01

The exposure of the skin to medical drugs, skin care products, cosmetics, and other chemicals renders information on xenobiotic-metabolizing enzymes (XME) in the skin highly interesting. Since the use of freshly excised human skin for experimental investigations meets with ethical and practical limitations, information on XME in models comes in the focus including non-human mammalian species and in vitro skin models. This review attempts to summarize the information available in the open scientific literature on XME in the skin of human, rat, mouse, guinea pig, and pig as well as human primary skin cells, human cell lines, and reconstructed human skin models. The most salient outcome is that much more research on cutaneous XME is needed for solid metabolism-dependent efficacy and safety predictions, and the cutaneous metabolism comparisons have to be viewed with caution. Keeping this fully in mind at least with respect to some cutaneous XME, some models may tentatively be considered to approximate reasonable closeness to human skin. For dermal absorption and for skin irritation among many contributing XME, esterase activity is of special importance, which in pig skin, some human cell lines, and reconstructed skin models appears reasonably close to human skin. With respect to genotoxicity and sensitization, activating XME are not yet judgeable, but reactive metabolite-reducing XME in primary human keratinocytes and several reconstructed human skin models appear reasonably close to human skin. For a more detailed delineation and discussion of the severe limitations see the "Overview and Conclusions" section in the end of this review.

Non-stochastic effects of different energy beta emitters on pig and mouse skin

International Nuclear Information System (INIS)

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

1982-01-01

In this collaborative study skin areas of various sizes were irradiated with different energy beta emitters. In the post-irradiation period fields were examined for erythema, desquamation, ulceration and dermal necrosis. The aim of the study is to determine the threshold doses for the different biological reactions as a function of the energy of the radiation and the size of skin field irradiated. At St. Bartholomew's Hospital and Oxford the irradiation of mouse and pig skin was carried out using strontium-90 and thulium-170 sources. In addition, mice were irradiated with thallium-204, a slightly lower energy beta emitter than thulium. (author)

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

International Nuclear Information System (INIS)

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

1981-01-01

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

Gravimetric analysis and differential scanning calorimetric studies on glycerin-induced skin hydration.

Science.gov (United States)

Lee, Ae-Ri Cho; Moon, Hee Kyung

2007-11-01

A thermal gravimetric analysis (TGA) and a differential scanning calorimetry (DSC) were carried out to characterize the water property and an alteration of lipid phase transition of stratum corneum (SC) by glycerin. In addition, the relationship between steady state skin permeation rate and skin hydration in various concentrations of glycerin was investigated. Water vapor absorption-desorption was studied in the hairless mouse stratum corneum. Dry SC samples were exposed to different conc. of glycerin (0-50%) followed by exposure to dry air and the change in weight property was monitored over time by use of TGA. In DSC study, significant decrease in DeltaH of the lipid transition in 10% glycerin and water treated sample: the heat of lipid transition of normal, water, 10% glycerin treated SC were 6.058, 4.412 and 4.316 mJ/mg, respectively. In 10% glycerin treated SCs, the Tc of water shifts around 129 degrees C, corresponding to the weakly bound secondary water. In 40% glycerin treated SC, the Tc of water shifts to 144 degrees C corresponding to strongly bound primary water. There was a good correlation between the hydration property of the skin and the steady state skin flux with the correlation coefficient (r2=0.94). As the hydration increased, the steady state flux increased. As glycerin concentration increased, hydration property decreased. High diffusivity induced by the hydration effect of glycerin and water could be the major contributing factor for the enhanced skin permeation of nicotinic acid (NA).

Association of Diet With Skin Histological Features in UV-B-Exposed Mice.

Science.gov (United States)

Bhattacharyya, Tapan K; Hsia, Yvonne; Weeks, David M; Dixon, Tatiana K; Lepe, Jessica; Thomas, J Regan

2017-09-01

Long-term exposure to solar radiation produces deleterious photoaging of the skin. It is not known if diet can influence skin photoaging. To study the influence of a calorie-restricted diet and an obesity diet in mice exposed to long-term UV-B irradiation to assess if there is an association between diet and histopathological response to UV-B irradiation. In this animal model study in an academic setting, the dorsal skin of SKH1 hairless mice receiving normal, calorie-restricted, and obesity diets was exposed to UV-B irradiation 3 times a week for 10 weeks and were compared with corresponding controls. The mice were placed in the following groups, with 8 animals in each group: (1) intact control (C) with regular diet and no UV-B exposure, (2) intact control with UV-B exposure (CR), (3) calorie-restricted diet (CrC), (4) calorie-restricted diet with UV-B exposure (CrR), (5) obesity diet (OC), and (6) obesity diet with UV-B exposure (OR). The experiment was conducted during October through December 2013. Tissue processing and histological analysis were completed in 2016. Histomorphometric analysis was performed on paraffin-embedded skin sections stained by histological and immunohistochemical methods for estimation of epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, mast cells, dermal cellularity, and adipose layer ratio. Changes in wrinkles were noted. Hairless female mice (age range, 6-8 weeks) were obtained. With a normal diet, changes from UV-B irradiation occurred in epidermal thickness, epidermal proliferating cell nuclear antigen index, collagen I, elastic fibers, fibroblasts, and mast cells, which were modestly influenced by an obesity diet. Calorie restriction influenced the skin in nonirradiated control animals, with higher values for most variables. After UV-B exposure in animals with calorie restriction, epidermal thickness was increased, but other variables were unaffected. Animals

Preclinical study of mouse pluripotent parthenogenetic embryonic stem cell derivatives for the construction of tissue-engineered skin equivalent.

Science.gov (United States)

Rao, Yang; Cui, Jihong; Yin, Lu; Liu, Wei; Liu, Wenguang; Sun, Mei; Yan, Xingrong; Wang, Ling; Chen, Fulin

2016-10-22

Embryonic stem cell (ESC) derivatives hold great promise for the construction of tissue-engineered skin equivalents (TESE). However, harvesting of ESCs destroys viable embryos and may lead to political and ethical concerns over their application. In the current study, we directed mouse parthenogenetic embryonic stem cells (pESCs) to differentiate into fibroblasts, constructed TESE, and evaluated its function in vivo. The stemness marker expression and the pluripotent differentiation ability of pESCs were tested. After embryoid body (EB) formation and adherence culture, mesenchymal stem cells (MSCs) were enriched and directed to differentiate into fibroblastic lineage. Characteristics of derived fibroblasts were assessed by quantitative real-time PCR and ELISA. Functional ability of the constructed TESE was tested by a mouse skin defects repair model. Mouse pESCs expressed stemness marker and could form teratoma containing three germ layers. MSCs could be enriched from outgrowths of EBs and directed to differentiate into fibroblastic lineage. These cells express a high level of growth factors including FGF, EGF, VEGF, TGF, PDGF, and IGF1, similar to those of ESC-derived fibroblasts and mouse fibroblasts. Seeded into collagen gels, the fibroblasts derived from pESCs could form TESE. Mouse skin defects could be successfully repaired 15 days after transplantation of TESE constructed by fibroblasts derived from pESCs. pESCs could be induced to differentiate into fibroblastic lineage, which could be applied to the construction of TESE and skin defect repair. Particularly, pESC derivatives avoid the limitations of political and ethical concerns, and provide a promising source for regenerative medicine.

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

Energy Technology Data Exchange (ETDEWEB)

Abel, E.L. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957 (United States); Boulware, S. [Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723 (United States); Fields, T.; McIvor, E.; Powell, K.L. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957 (United States); DiGiovanni, J.; Vasquez, K.M. [Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723 (United States); MacLeod, M.C., E-mail: mcmacleod@mdanderson.org [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957 (United States)

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.

Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction

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Ji-Eun Park

2017-01-01

Full Text Available Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE on H2O2-stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence-associated β-galactosidase activation. KPE inhibited the expression of cell-cycle inhibitors (p53, p21, p16, and pRb and stimulated the expression of cell-cycle activators (E2F1 and E2F2. H2O2-induced hyperactivation of the phosphatidylinositol 3-kinase/protein kinase B (AKT signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a and mammalian target of rapamycin (mTOR. KPE attenuated inflammatory mediators (interleukin-6 (IL-6, IL-8, nuclear factor kappa B (NF-κB, and cyclooxygenase-2 (COX-2 and increased the mRNA expression of PGC-1α, ERRα, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent.

A synthetic C16 omega-hydroxyphytoceramide improves skin barrier functions from diversely perturbed epidermal conditions.

Science.gov (United States)

Oh, Myoung Jin; Nam, Jin Ju; Lee, Eun Ok; Kim, Jin Wook; Park, Chang Seo

2016-10-01

Omega-hydroxyceramides (ω-OH-Cer) play a crucial role in maintaining the integrity of skin barrier. ω-OH-Cer are the primary lipid constituents of the corneocyte lipid envelope (CLE) covalently attached to the outer surface of the cornified envelope linked to involucrin to become bound form lipids in stratum corneum (SC). CLE becomes a hydrophobic impermeable layer of matured corneocyte preventing loss of natural moisturizing factor inside the corneocytes. More importantly, CLE may also play an important role in the formation of proper orientation of intercellular lipid lamellar structure by interdigitating with the intercellular lipids in a comb-like fashion. Abnormal barrier conditions associated with atopic dermatitis but also UVB-irradiated skins are known to have lowered level of bound lipids, especially ω-OH-Cer, which indicate that ω-OH-Cer play an important role in maintaining the integrity of skin barrier. In this study, protective effects of a novel synthetic C16 omega-hydroxyphytoceramides (ω-OH-phytoceramide) on skin barrier function were investigated. Epidermal barrier disruption was induced by UVB irradiation, tape-stripping in hairless mouse and human skin. Protective effect of damaged epidermis was evaluated using the measurement of transepidermal water loss and cohesion of SC. Increased keratinocyte differentiation was verified using cultured keratinocyte through western blot. Results clearly demonstrated that a synthetic C16 ω-OH-phytoceramide enhanced the integrity of SC and accelerated the recovery of damaged skin barrier function by stimulating differentiation process. In a conclusion, a synthetic C16 ω-OH-phytoceramide treatment improved epidermal homeostasis in several disrupted conditions.

Hydrogel-based ultra-moisturizing cream formulation for skin hydration and enhanced dermal drug delivery.

Science.gov (United States)

Lee, Sang Gon; Kim, Sung Rae; Cho, Hye In; Kang, Mean Hyung; Yeom, Dong Woo; Lee, Seo Hyun; Lee, Sangkil; Choi, Young Wook

2014-01-01

To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (∆AU) was in the order of HUMC2>HUMC1 ≥ CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm(2)) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm(2)) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs.

Protoporphyrin IX fluorescence kinetics and localization after topical application of ALA pentyl ester and ALA on hairless mouse skin with UVB-induced early skin cancer

NARCIS (Netherlands)

van den Akker, J. T.; de Bruijn, H. S.; Beijersbergen van Henegouwen, G. M.; Star, W. M.; Sterenborg, H. J.

2000-01-01

In order to improve the efficacy of 5-aminolevulinic acid-based (ALA) photodynamic therapy (PDT), different ALA derivatives are presently being investigated. ALA esters are more lipophilic and therefore may have better skin penetration properties than ALA, possibly resulting in enhanced

Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway

International Nuclear Information System (INIS)

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

2014-01-01

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 [ 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

Chemical peeling by SA-PEG remodels photo-damaged skin: suppressing p53 expression and normalizing keratinocyte differentiation.

Science.gov (United States)

Dainichi, Teruki; Amano, Satoshi; Matsunaga, Yukiko; Iriyama, Shunsuke; Hirao, Tetsuji; Hariya, Takeshi; Hibino, Toshihiko; Katagiri, Chika; Takahashi, Motoji; Ueda, Setsuko; Furue, Masutaka

2006-02-01

Chemical peeling with salicylic acid in polyethylene glycol vehicle (SA-PEG), which specifically acts on the stratum corneum, suppresses the development of skin tumors in UVB-irradiated hairless mice. To elucidate the mechanism through which chemical peeling with SA-PEG suppresses skin tumor development, the effects of chemical peeling on photodamaged keratinocytes and cornified envelopes (CEs) were evaluated in vivo. Among UVB-irradiated hairless mice, the structural atypia and expression of p53 protein in keratinocytes induced by UVB irradiation were intensely suppressed in the SA-PEG-treated mice 28 days after the start of weekly SA-PEG treatments when compared to that in the control UVB-irradiated mice. Incomplete expression of filaggrin and loricrin in keratinocytes from the control mice was also improved in keratinocytes from the SA-PEG-treated mice. In photo-exposed human facial skin, immature CEs were replaced with mature CEs 4 weeks after treatment with SA-PEG. Restoration of photodamaged stratum corneum by treatment with SA-PEG, which may affect remodeling of the structural environment of the keratinocytes, involved the normalization of keratinocyte differentiation and suppression of skin tumor development. These results suggest that the stratum corneum plays a protective role against carcinogenesis, and provide a novel strategy for the prevention of photo-induced skin tumors.

The response of previously irradiated mouse skin to heat alone or combined with irradiation: influence of thermotolerance

NARCIS (Netherlands)

Wondergem, J.; Haveman, J.

1983-01-01

The skin of the mouse foot was used to study the effects of previous irradiation on the response to hyperthermia (44 degrees C), to irradiation, or to irradiation combined with hyperthermia (43 degrees C or 44 degrees C). Hyperthermia was applied by immersing the mouse foot into a hot waterbath and

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

Science.gov (United States)

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...

Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery.

Science.gov (United States)

Balakrishnan, Prabagar; Shanmugam, Srinivasan; Lee, Won Seok; Lee, Won Mo; Kim, Jong Oh; Oh, Dong Hoon; Kim, Dae-Duk; Kim, Jung Sun; Yoo, Bong Kyu; Choi, Han-Gon; Woo, Jong Soo; Yong, Chul Soon

2009-07-30

Niosomes have been reported as a possible approach to improve the low skin penetration and bioavailability characteristics shown by conventional topical vehicle for minoxidil. Niosomes formed from polyoxyethylene alkyl ethers (Brij) or sorbitan monoesters (Span) with cholesterol molar ratios of 0, 1 and 1.5 were prepared with varying drug amount 20-50mg using thin film-hydration method. The prepared systems were characterized for entrapment efficiency, particle size, zeta potential and stability. Skin permeation studies were performed using static vertical diffusion Franz cells and hairless mouse skin treated with either niosomes, control minoxidil solution (propylene glycol-water-ethanol at 20:30:50, v/v/v) or a leading topical minoxidil commercial formulation (Minoxyl). The results showed that the type of surfactant, cholesterol and incorporated amount of drug altered the entrapment efficiency of niosomes. Higher entrapment efficiency was obtained with the niosomes prepared from Span 60 and cholesterol at 1:1 molar ratio using 25mg drug. Niosomal formulations have shown a fairly high retention of minoxidil inside the vesicles (80%) at refrigerated temperature up to a period of 3 months. It was observed that both dialyzed and non-dialyzed niosomal formulations (1.03+/-0.18 to 19.41+/-4.04%) enhanced the percentage of dose accumulated in the skin compared to commercial and control formulations (0.11+/-0.03 to 0.48+/-0.17%) except dialyzed Span 60 niosomes. The greatest skin accumulation was always obtained with non-dialyzed vesicular formulations. Our results suggest that these niosomal formulations could constitute a promising approach for the topical delivery of minoxidil in hair loss treatment.

Expression and significance of Bax protein in model of radiation injury in mouse skin

International Nuclear Information System (INIS)

Feng Yizhong; Mo Yahong

2002-01-01

Objective: The study is to find some valuable criteria for diagnosis and treatment of radiation injury in skin. Methods: The expression of Bax protein was studied by SP immunohistochemistry in 40 cases of model of radiation injury in mouse skin. Their relationship relating to radiation dose was also investigated. Results: The expression rates of Bax were 30%, 30%, 70%, 70% in 5 Gy group, 15 Gy group, 30 Gy group, 45 Gy group respectively. There was no significant correlation between the expression of Bax and radiation groups. Conclusions: The experiment shows that radiation can increase the expression of Bax protein which might be related to poor healing in radiation skin injury

Excision of pyrimidine dimers from epidermal DNA and nonsemiconservative epidermal DNA synthesis following ultraviolet irradiation of mouse skin

International Nuclear Information System (INIS)

Bowden, G.T.; Trosko, J.E.; Shapas, B.G.; Boutwell, R.K.

1975-01-01

Pyrimidine dimer production and excision in epidermal DNA were studied at five different dose levels of ultraviolet light in the skin of intact mice. Dimer production increased with dose up to 50,400 ergs/sq mm. Approximately 30 percent of the thymine-containing dimers were excised by 24 hr after irradiation at three lower dose levels of ultraviolet light. Nonsemiconservative DNA replication in ultraviolet-irradiated mouse skin was shown to continue for at least 18 hr. The rate of nonsemiconservative replication decreased with time, but did so slowly. The initial rates of nonsemiconservative replication increased with ultraviolet light dose levels up to about 4200 ergs/sq mm, after which the initial rates were decreased. Semiconservative epidermal DNA synthesis was shown to be inhibited by hydroxyurea, but hydroxyurea had no effect on ultraviolet light-induced nonsemiconservative DNA replication. The observed pyrimidine dimer excision and nonsemiconservative DNA replication suggest that in the intact mouse the cells of the epidermis are capable of DNA excision repair after ultraviolet irradiation of mouse skin

Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

Directory of Open Access Journals (Sweden)

Vishnu Hosur

2017-08-01

Full Text Available In humans, gain-of-function (GOF mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis.

In vitro skin permeation and anti-atopic efficacy of lipid nanocarriers containing water soluble extracts of Houttuynia cordata.

Science.gov (United States)

Kwon, Taek Kwan; Kim, Jin-Chul

2014-10-01

The aims of this work are to enhance the in vitro skin permeation of Houttuynia cordata (water-soluble extract of H. cordata; HCWSE) and to boost the efficacy of HCWSE against atopic dermatitis (AD) - like skin lesion in hairless mice using lipid nano-carriers (liposome and cubosome). HCWSE was obtained by a hot water extraction. Monoolein cubosomal suspension containing HCWSE and egg phosphatidylcholine liposomal suspension containing the same was prepared by a sonication and a film hydration method, respectively. The lipid nano-carriers, especially cubosome, enhanced the in vitro skin permeation of HCWSE. The inhibitory effects of HCWSE-containing lipid carrier suspensions on the development of 1-chloro-2,4-dinitrobenzene (DNCB)-induced AD-like skin lesion in hairless mice were investigated by observing appearance of skin surface, serum immunoglobulin E (IgE) level and cytokine expression. HCWSE-containing preparations suppressed IgE production and interleukin 4 expression, whereas they promoted interferon gamma expression. The order of lymphocyte (B-cell, Th1 cell and Th2 cell) modulating effect was HCWSE-containing cubosomal suspension > HCWSE-containing liposomal suspension > HCWSE solution in phosphate buffered saline, indicating that the cubosomal suspension, among the preparations, was the most efficacious in inhibiting the development of DNCB-induced AD-like skin lesion. It is believed that the cubosomal suspension containing HCWSE would be an efficacious preparation for the treatment of AD.

Diseño y construcción de un péptido con potencial inmunogénico a partir del dominio de unión a supresor de hairless de la proteína hairless de Drosophila melanogaster

Directory of Open Access Journals (Sweden)

Humberto Contreras Cornejo

2011-01-01

Full Text Available Las funciones de los diferentes tipos de células que constituyen un organismo multicelular, son reguladas mediante vías de transducción de señales, cuyo objetivo final es la regulación de genes blanco. La vía de señalización Notch participa principalmente en el desarrollo temprano y tardío del embrión, y en menor grado en el funcionamiento correcto del individuo. Hairless es una proteína involucrada en la vía de señalización Notch y su papel es modular negativamente la vía. A pesar de los esfuerzos realizados para detectar a hairless en animales superiores, no se ha logrado identificar un homólogo de la misma. Su identificación es fundamental para entender mejor los procesos de regulación de la vía, del desarrollo embrionario y de otros procesos patológicos que involucran a Notch. Los homólogos de Hairless en insectos poseen al menos tres dominios altamente conservados, de los cuales el dominio de unión a Supresor de hairless, una proteína propia de la vía, es el más conservado. Mediante análisis in silico y técnicas de biología molecular se identificó y delimitó un péptido con potencial inmunogénico del dominio de unión a Supresor de hairless de la proteína hairless de Drosophila melanogaster. Este péptido se usó como antígeno en gallinas, para generar anticuerpos policlonales. Los sueros se probaron contra extracto total de proteína de embriones de la mosca de la fruta.

Photocarcinogenesis and toxicity of benzoyl peroxide in hairless mice after simulated solar radiation

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas

2010-01-01

with UV radiation. BPO can promote skin tumorigenesis in a mouse skin chemical carcinogenesis model. As acne vulgaris is frequently localized on sun-exposed areas, we investigated whether BPO or BPO-clin accelerates photocarcinogenesis in combination with simulated solar radiation (SSR) in 12 groups of 25...

Epithelial cell kinetics in mouse and rat skin irradiated with electrons

International Nuclear Information System (INIS)

McMaster-Schuyler, L.

1984-02-01

Experiments were performed to examine the kinetic responses of mouse and rat epidermal cells in vivo after single doses of ionizing radiation including responses of hair follicles at times after irradiation. The labeling indices in both species were reduced to 30 to 50% of control values immediately following irradiation at all the doses. In the rat, the labeling indices recovered and overshot control values within the first three days after 300 to 1200 rads. The mouse labeling indices continued to be suppressed for up to 10 days after 300 to 2400 rads. This indicated that rat G 1 phase epidermal cells recovered three times faster than those of the mouse with respect to the ability to maintain or increase control level cell proliferation after irradiation. After 1800 and 2400 rads, doses which produce skin ulceration, both species showed a reduction in their labeling indices for up to 7 days, indicating that a dose-dependent mechanism of recovery may be operable in the rat. 99 refs., 15 figs., 6 tabs

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

Science.gov (United States)

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.

Quantification of tumour initiating effect of jute batching oil and its distillates over mouse skin.

Science.gov (United States)

Agarwal, R; Kumar, S; Shukla, Y; Antony, M; Mehrotra, N K

1985-09-30

In order to identify the tumour initiating constituent(s) of a mineral oil, jute batching oil (JBO), used in the processing of jute fibres, it was fractionally distilled in various boiling range fractions. The latter were then subjected to in vivo assessment of their aryl hydrocarbon hydroxylase (AHH) inducing potential in mouse epidermis. Fractions with almost similar AHH inducing potential were regrouped and studied for their tumour initiating potential over mouse skin following two-stage initiation-promotion protocol and using 12-O-tetradecanoyl phorbol-13-acetate (TPA) as tumour promoter. It was noticed that: (1) JBO as initiator, provoked local development of benign skin tumours over mouse back; (2) fractions of JBO boiling below 335 degrees C and above 399 degrees C accounted for most of the tumour initiating potential of the oil; (3) the histological features of the tumours (i.e. benign papillomas and keratoacanthomas) initiated by these fractions were similar to those developed after being initiated with unfractionated or reconstituted JBO; (4) removal of these fractions from JBO may be attempted which could decontaminate the batch oil from most of its tumorigenic components and make it safer for industrial use.

Identification of skin-expressed genes possibly associated with wool growth regulation of Aohan fine wool sheep

OpenAIRE

Liu, Nan; Li, Hegang; Liu, Kaidong; Yu, Juanjuan; Bu, Ran; Cheng, Ming; De, Wei; Liu, Jifeng; He, Guangling; Zhao, Jinshan

2014-01-01

Background Sheep are valuable resources for the animal fibre industry. Therefore, identifying genes which regulate wool growth would offer strategies for improving the quality of fine wool. In this study, we employed Agilent sheep gene expression microarray and proteomic technology to compare the gene expression patterns of the body side (hair-rich) and groin (hairless) skins of Aohan fine wool sheep (a Chinese indigenous breed). Results Comparing the body side to the groin skins (S/G) of Aoh...

Is lack of sleep capable of inducing DNA damage in aged skin?

Science.gov (United States)

Kahan, V; Ribeiro, D A; Egydio, F; Barros, L A; Tomimori, J; Tufik, S; Andersen, M L

2014-01-01

Skin naturally changes with age, becoming more fragile. Various stimuli can alter skin integrity. The aim of this study was to evaluate whether sleep deprivation affects the integrity of DNA in skin and exacerbates the effects of aging. Fifteen-month old female Hairless mice underwent 72 h of paradoxical sleep deprivation or 15 days of chronic sleep restriction. Punch biopsies of the skin were taken to evaluate DNA damage by single cell gel (comet) assay. Neither paradoxical sleep deprivation nor sleep restriction increased genetic damage, measured by tail movement and tail intensity values. Taken together, the findings are consistent with the notion that aging overrides the effect of sleep loss on the genetic damage in elderly mice. © 2014 S. Karger AG, Basel.

Cell death induced on cell cultures and nude mouse skin by non-thermal, nanosecond-pulsed generated plasma.

Directory of Open Access Journals (Sweden)

Arnaud Duval

Full Text Available Non-thermal plasmas are gaseous mixtures of molecules, radicals, and excited species with a small proportion of ions and energetic electrons. Non-thermal plasmas can be generated with any high electro-magnetic field. We studied here the pathological effects, and in particular cell death, induced by nanosecond-pulsed high voltage generated plasmas homogeneously applied on cell cultures and nude mouse skin. In vitro, Jurkat cells and HMEC exhibited apoptosis and necrosis, in dose-dependent manner. In vivo, on nude mouse skin, cell death occurred for doses above 113 J/cm(2 for the epidermis, 281 J/cm(2 for the dermis, and 394 J/cm(2 for the hypodermis. Using electron microscopy, we characterized apoptosis for low doses and necrosis for high doses. We demonstrated that these effects were not related to thermal, photonic or pH variations, and were due to the production of free radicals. The ability of cold plasmas to generate apoptosis on cells in suspension and, without any sensitizer, on precise skin areas, opens new fields of application in dermatology for extracorporeal blood cell treatment and the eradication of superficial skin lesions.

Generation of New Hairless Alleles by Genomic Engineering at the Hairless Locus in Drosophila melanogaster.

Directory of Open Access Journals (Sweden)

Heiko Praxenthaler

Full Text Available Hairless (H is the major antagonist within the Notch signalling pathway of Drosophila melanogaster. By binding to Suppressor of Hairless [Su(H] and two co-repressors, H induces silencing of Notch target genes in the absence of Notch signals. We have applied genomic engineering to create several new H alleles. To this end the endogenous H locus was replaced with an attP site by homologous recombination, serving as a landing platform for subsequent site directed integration of different H constructs. This way we generated a complete H knock out allele HattP, reintroduced a wild type H genomic and a cDNA-construct (Hgwt, Hcwt as well as two constructs encoding H proteins defective of Su(H binding (HLD, HiD. Phenotypes regarding viability, bristle and wing development were recorded, and the expression of Notch target genes wingless and cut was analysed in mutant wing discs or in mutant cell clones. Moreover, genetic interactions with Notch (N5419 and Delta (DlB2 mutants were addressed. Overall, phenotypes were largely as expected: both HLD and HiD were similar to the HattP null allele, indicating that most of H activity requires the binding of Su(H. Both rescue constructs Hgwt and Hcwt were homozygous viable without phenotype. Unexpectedly, the hemizygous condition uncovered that they were not identical to the wild type allele: notably Hcwt showed a markedly reduced activity, suggesting the presence of as yet unidentified regulatory or stabilizing elements in untranslated regions of the H gene. Interestingly, Hgwt homozygous cells expressed higher levels of H protein, perhaps unravelling gene-by-environment interactions.

Fluoxetine ameliorates atopic dermatitis-like skin lesions in BALB/c mice through reducing psychological stress and inflammatory response

Directory of Open Access Journals (Sweden)

Yanxi Li

2016-09-01

Full Text Available Atopic dermatitis (AD is a common chronic inflammatory skin disorder, and patients with AD suffer from severe psychological stress, which markedly increases the prevalence rate of depression and anxiety disorders in later life. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been reported to exert anti-inflammatory and immunosuppressive effects. However, it is unclear whether fluoxetine is effective in the treatment of AD through reducing psychological stress and inflammatory reaction. Here, we reported that a BALB/c mouse model of AD was induced by application of 2,4‑dinitrochlorobenzene (DNCB onto hairless dorsal skin. Chronic fluoxetine treatment (10 mg/kg per day, i.p. significantly attenuated AD-like symptoms, as reflected by a dramatic decrease in scratching bouts, as well as a decrease in anxiety- and depressive-like behaviors. Furthermore, these behavioral changes were accompanied by a significant decrease in epidermal thickness, the number of mast cells in skin tissue, mRNA levels of interleukin-4 (IL-4 and IL-13 in the spleen, as well as serum immunoglobulin E (IgE in the DNCB-treated mice by treatment with fluoxetine. Taken together, these results indicate that fluoxetine may suppress psychological stress and inflammatory response during AD development, and subsequently ameliorate AD symptoms, suggesting that fluoxetine may be a potential therapeutic agent against AD in clinic.

Nephrogenic systemic fibrosis: late skin manifestations

DEFF Research Database (Denmark)

Bangsgaard, Nannie; Marckmann, Peter; Rossen, Kristian

2009-01-01

BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a serious disease that occurs in patients with severe renal disease and is believed to be caused by gadolinium-containing contrast agents. A detailed description of the late skin manifestations of NSF is important to help dermatologists...... and nephrologists recognize the disease. OBSERVATIONS: We studied 17 patients with NSF late in the disease. All patients showed epidermal atrophy and hairlessness of the affected regions, primarily the lower legs. Affected areas were symmetrically distributed and hyperpigmented in most cases. Eleven patients showed......: This descriptive case series of patients with NSF gives a detailed clinical picture of the skin manifestations late in the disease. It demonstrates that the clinical picture in the late stage has a varied presentation and that NSF has a significant effect on the quality of life....

Development and characterization of novel 1-(1-Naphthyl)piperazine-loaded lipid vesicles for prevention of UV-induced skin inflammation.

Science.gov (United States)

Menezes, Ana Catarina; Campos, Patrícia Mazureki; Euletério, Carla; Simões, Sandra; Praça, Fabíola Silva Garcia; Bentley, Maria Vitória Lopes Badra; Ascenso, Andreia

2016-07-01

1-(1-Naphthyl)piperazine (1-NPZ) has shown promising effects by inhibiting UV radiation-induced immunosuppression. Ultradeformable vesicles are recent advantageous systems capable of improving the (trans)dermal drug delivery. The aim of this study was to investigate 1-NPZ-loaded transethosomes (NPZ-TE) and 1-NPZ-loaded vesicles containing dimethyl sulfoxide (NPZ-DM) as novel delivery nanosystems, and to uncover their chemopreventive effect against UV-induced acute inflammation. Their physicochemical properties were evaluated as follows: vesicles size and zeta potential by dynamic and electrophoretic light scattering, respectively; vesicle deformability by pressure driven transport; rheological behavior by measuring viscosity and I-NPZ entrapment yield by HPLC. In vitro topical delivery studies were performed in order to evaluate the permeation profile of both formulations, whereas in vivo studies sought to assess the photoprotective effect of the selected formulation on irradiated hairless mice by measuring myeloperoxidase activity and the secretion of proinflammatory cytokines. Either NPZ-TE or NPZ-DM exhibited positive results in terms of physicochemical properties. In vitro data revealed an improved permeation of 1-NPZ across pig ear skin, especially by NPZ-DM. In vivo studies demonstrated that NPZ-DM exposure was capable of preventing UVB-induced inflammation and blocking mediators of inflammation in mouse skin. The successful results here obtained encourage us to continue these studies for the management of inflammatory skin conditions that may lead to the development of skin cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Photoprotective effects of methoxycinnamidopropyl polysilsesquioxane.

Science.gov (United States)

Choi, Dae-Kyoung; Jung, Taek Kyu; Lim, Tae-Yeon; Kim, Tae-Heung; Kim, Young Baek; Lee, Jeung-Hoon; Yoon, Kyung-Sup; Yoon, Tae-Jin

2011-01-01

A new sunscreen ingredient, methoxycinnamidopropyl polysilsesquioxane (MCP-PSQ), which contains an UV-absorbing p-methoxycinnamoyl group, has been developed synthetically and evaluated using in vitro and in vivo approaches. Previous studies revealed that MCP-PSQ has a raising or boosting effect on the sun protection factor (SPF) of other sunscreen agents. In this study, we demonstrated that MCP-PSQ, an organic/inorganic hybrid compound, has photoprotective effects for human fibroblasts, and for hairless mouse and human skin. MCP-PSQ increases cell viability and suppresses the expression of p53 protein in fibroblasts after UV exposure. In addition, the numbers of sunburn cells and mast cells are reduced by topical application of MCP-PSQ on hairless mouse skin after UV irradiation. A 10% MCP-PSQ cream has higher and similar effects on SPF values for human skin compared to 5% titanium dioxide (TiO(2)) and 5% ethylhexyl methoxycinnamate (EHMC), respectively. The SPF value obtained using the MCP-PSQ cream did not drop after UV irradiation of the cream itself. However, higher dose of UV irradiation is required to guarantee the stability or photostability of the formulation. Further, there were no side effects such as erythema, edema, itch or tingling, suggesting that MCP-PSQ is a good sunscreen agent. © 2011 The Authors. Photochemistry and Photobiology © 2011 The American Society of Photobiology.

Dietary Cerebroside from Sea Cucumber (Stichopus japonicus): Absorption and Effects on Skin Barrier and Cecal Short-Chain Fatty Acids.

Science.gov (United States)

Duan, Jingjing; Ishida, Marina; Aida, Kazuhiko; Tsuduki, Tsuyoshi; Zhang, Jin; Manabe, Yuki; Hirata, Takashi; Sugawara, Tatsuya

2016-09-21

Sphingolipids from marine sources have attracted more attention recently because of their distinctive structures and expected functions. In this study, the content and components of cerebroside from sea cucumber Stichopus japonicus were analyzed. The absorption of cerebroside from S. japonicus was investigated with an in vivo lipid absorption assay. The result revealed that S. japonicus is a rich source of cerebroside that contained considerable amounts of odd carbon chain sphingoid bases. The cumulative recoveries of d17:1- and d19:2-containing cerebrosides were 0.31 ± 0.16 and 0.32 ± 0.10%, respectively, for 24 h after administration. To the best of the authors' knowledge, this is the first work that shows sphingolipids from a marine source could be absorbed in vivo and incorporated into ceramides. In addition, dietary supplementation with sea cucumber cerebroside to hairless mouse improved the skin barrier function and increased short-chain fatty acids in cecal contents, which have shown beneficial effects on the host.

Strain differences in mouse skin carcinogenesis experiments using ionizing radiation and the tumor promoter TPA

International Nuclear Information System (INIS)

Jaffe, D.R.; Bowden, G.T.

1985-01-01

Ionizing radiation has been shown to be a complete carcinogen in rodent skin when administered repeatedly. The initiating potential of ionizing radiation in mouse skin was tested in a classical two-stage protocol in both CD-1 and Sencar mice. Beta radiation (0.5, 1.5, 3.0 and 5.0 Gy) was administered by a strontium 90 applicator followed two weeks later by twice weekly application of 5 μg TPA. A statistical difference in the papilloma incidence between radiation initiated, TPA promoted versus non-initiated TPA promoted groups was not found (25-35% animals with papillomas and 0.35-0.45 papillomas per mouse at 65 weeks of promotion for both initiated and non-initiated mice). There appeared to be no strain differences between the CD-1 and Sencar in response to the initiating effects if ionizing radiation. This is in direct contrast to the studies showing Sencar mice to be much more sensitive than CD-1 to the initiating effects of chemical carcinogens

Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes.

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Hsieh, Jui-Cheng; Estess, Rudolf C; Kaneko, Ichiro; Whitfield, G Kerr; Jurutka, Peter W; Haussler, Mark R

2014-02-01

The vitamin D receptor (VDR), but not its hormonal ligand, 1,25-dihydroxyvitamin D3 (1,25D), is required for the progression of the mammalian hair cycle. We studied three genes relevant to hair cycle signaling, DKKL1 (Soggy), SOSTDC1 (Wise), and HR (Hairless), to determine whether their expression is regulated by VDR and/or its 1,25D ligand. DKKL1 mRNA was repressed 49-72% by 1,25D in primary human and CCD-1106 KERTr keratinocytes; a functional vitamin D responsive element (VDRE) was identified at -9590 bp in murine Soggy. Similarly, SOSTDC1 mRNA was repressed 41-59% by 1,25D in KERTr and primary human keratinocytes; a functional VDRE was located at -6215 bp in human Wise. In contrast, HR mRNA was upregulated 1.56- to 2.77-fold by 1,25D in primary human and KERTr keratinocytes; a VDRE (TGGTGAgtgAGGACA) consisting of an imperfect direct repeat separated by three nucleotides (DR3) was identified at -7269 bp in the human Hairless gene that mediated dramatic induction, even in the absence of 1,25D ligand. In parallel, a DR4 thyroid hormone responsive element, TGGTGAggccAGGACA, was identified at +1304 bp in the human HR gene that conferred tri-iodothyronine (T3)-independent transcriptional activation. Because the thyroid hormone receptor controls HR expression in the CNS, whereas VDR functions in concert with the HR corepressor specifically in skin, a model is proposed wherein unliganded VDR upregulates the expression of HR, the gene product of which acts as a downstream comodulator to feedback-repress DKKL1 and SOSTDC1, resulting in integration of bone morphogenic protein and Wnt signaling to drive the mammalian hair cycle and/or influencing epidermal function.

NCBI nr-aa BLAST: CBRC-CJAC-01-1133 [SEVENS

Lifescience Database Archive (English)

Full Text Available CBRC-CJAC-01-1133 ref|NP_068677.2| hairless protein [Mus musculus] sp|Q61645|HAIR_MOUSE Protein hair...less gb|AAH49182.1| Hairless [Mus musculus] gb|EDL35888.1| hairless, isoform CRA_a [Mus musculus] gb|EDL35889.1| hai...rless, isoform CRA_a [Mus musculus] gb|EDL35890.1| hairless, isoform CRA_a [Mus musculus] NP_068677.2 5.1 44% ...

Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program.

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John P Sundberg

Full Text Available The International Knockout Mouse Consortium was formed in 2007 to inactivate ("knockout" all protein-coding genes in the mouse genome in embryonic stem cells. Production and characterization of these mice, now underway, has generated and phenotyped 3,100 strains with knockout alleles. Skin and adnexa diseases are best defined at the gross clinical level and by histopathology. Representative retired breeders had skin collected from the back, abdomen, eyelids, muzzle, ears, tail, and lower limbs including the nails. To date, 169 novel mutant lines were reviewed and of these, only one was found to have a relatively minor sebaceous gland abnormality associated with follicular dystrophy. The B6N(Cg-Far2tm2b(KOMPWtsi/2J strain, had lesions affecting sebaceous glands with what appeared to be a secondary follicular dystrophy. A second line, B6N(Cg-Ppp1r9btm1.1(KOMPVlcg/J, had follicular dystrophy limited to many but not all mystacial vibrissae in heterozygous but not homozygous mutant mice, suggesting that this was a nonspecific background lesion. We discuss potential reasons for the low frequency of skin and adnexal phenotypes in mice from this project in comparison to those seen in human Mendelian diseases, and suggest alternative approaches to identification of human disease-relevant models.

Preventive effect of chemical peeling on ultraviolet induced skin tumor formation.

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Abdel-Daim, Mohamed; Funasaka, Yoko; Kamo, Tsuneyoshi; Ooe, Masahiko; Matsunaka, Hiroshi; Yanagita, Emmy; Itoh, Tomoo; Nishigori, Chikako

2010-10-01

Chemical peeling is one of the dermatological treatments available for certain cutaneous diseases and conditions or improvement of cosmetic appearance of photoaged skin. We assessed the photochemopreventive effect of several clinically used chemical peeling agents on the ultraviolet (UV)-irradiated skin of hairless mice. Chemical peeling was done using 35% glycolic acid dissolved in distilled water, 30% salicylic acid in ethanol, 10% or 35% trichloroacetic acid (TCA) in distilled water at the right back of UV-irradiated hairless mice every 2 weeks in case of glycolic acid, salicylic acid, and 10% TCA and every 4 weeks in case of 35% TCA for totally 18 weeks after the establishment of photoaged mice by irradiation with UVA+B range light three times a week for 10 weeks at a total dose of 420 J/cm(2) at UVA and 9.6 J/cm(2) at UVB. Tumor formation was assessed every week. Skin specimens were taken from treated and non-treated area for evaluation under microscopy, evaluation of P53 expression, and mRNA expression of cyclooxygenase (COX)-2. Serum level of prostaglandin E(2) was also evaluated. All types of chemical peeling reduced tumor formation in treated mice, mostly in the treated area but also non-treated area. Peeling suppressed clonal retention of p53 positive abnormal cells and reduced mRNA expression of COX-2 in treated skin. Further, serum prostaglandin E(2) level was decreased in chemical peeling treated mice. These results indicate that chemical peeling with glycolic acid, salicylic acid, and TCA could serve tumor prevention by removing photodamaged cells. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

An Improved Mouse Model of Atopic Dermatitis and Suppression of Skin Lesions by an Inhibitor of Tec Family Kinases

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Yuko Kawakami

2007-01-01

Conclusions: We established a highly efficient, highly reproducible protocol to induce skin lesions in NC/Nga mice and successfully applied it to show the efficacy of terreic acid in treating skin lesions. This mouse model of atopic dermatitis will be useful to study the pathogenetic processes of atopic dermatitis and to evaluate the efficacy of drug candidates.

Brief communication: Hair density and body mass in mammals and the evolution of human hairlessness.

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Sandel, Aaron A

2013-09-01

Humans are unusual among mammals in appearing hairless. Several hypotheses propose explanations for this phenotype, but few data are available to test these hypotheses. To elucidate the evolutionary history of human "hairlessness," a comparative approach is needed. One previous study on primate hair density concluded that great apes have systematically less dense hair than smaller primates. While there is a negative correlation between body size and hair density, it remains unclear whether great apes have less dense hair than is expected for their body size. To revisit the scaling relationship between hair density and body size in mammals, I compiled data from the literature on 23 primates and 29 nonprimate mammals and conducted Phylogenetic Generalized Least Squares regressions. Among anthropoids, there is a significant negative correlation between hair density and body mass. Chimpanzees display the largest residuals, exhibiting less dense hair than is expected for their body size. There is a negative correlation between hair density and body mass among the broader mammalian sample, although the functional significance of this scaling relationship remains to be tested. Results indicate that all primates, and chimpanzees in particular, are relatively hairless compared to other mammals. This suggests that there may have been selective pressures acting on the ancestor of humans and chimpanzees that led to an initial reduction in hair density. To further understand the evolution of human hairlessness, a systematic study of hair density and physiology in a wide range of species is necessary. Copyright © 2013 Wiley Periodicals, Inc.

Comparison of ultraviolet light-induced skin carcinogenesis and ornithine decarboxylase activity in sencar and hairless SKH-1 mice fed a constant level of dietary lipid varying in corn and coconut oil

International Nuclear Information System (INIS)

Berton, T.R.; Fischer, S.M.; Conti, C.J.; Locniskar, M.F.

1996-01-01

To investigate the effect of various levels of corn oil and coconut oil on ultraviolet (UV) light‐induced skin tumorigenesis and ornithine decarboxylase (ODC) activity, Sencar and SKH‐1 mice were fed one of three 15% (weight) fat semipurified diets containing three ratios of com oil to coconut oil: 1.0%:14.0%, 7.9%:7.1%, and 15.0%:0.0% in Diets A, B, and C, respectively. Groups of 30 Sencar and SKH‐1 mice were fed one of the diets for three weeks before UV irradiation; then both strains were UV irradiated with an initial dose of 90 mJ/cm2. The dose was given three times a week and increased 25% each week. For Sencar mice (irradiated 33 wks for a total dose of 48 J/cm2), tumor incidence reached a maximum of 60%, 60%, and 53% for Diets A, B, and C, respectively, with an overall average of one to two tumors per tumor‐bearing animal. For the SKH‐1 mice (irradiated 29 wks for a total dose of 18 J/cm2), all diet groups reached 100% incidence by 29 weeks, with approximately 12 tumors per tumor‐bearing mouse. No significant effect of dietary corn oil/coconut oil was found for tumor latency, incidence, or yield in either strain. The effect of increasing com oil on epidermal ODC activity in chronically UV‐irradiated Sencar and SKH‐1 mice was assessed Three groups of mice from each strain were fed one of the experimental diets and UV irradiated for six weeks. Sencar mice showed no increase in ODC activity until six weeks of treatment, when the levels of ODC activity in the UV‐irradiated mice fed Diet A were significantly higher than those in mice fed Diet B or Diet C: 1.27, 0.55, and 0.52 nmol/mg protein/hr, respectively. In the SKH‐1 mice, ODC activity was increased by the first week of UV treatment, and by three weeks of treatment a dietary effect was observed: ODC activity was significantly higher in mice fed Diet C (0.70 nmol/mg protein/hr) than in mice fed Diet A (0.18 nmol/mg protein/hr). Although there was no significant effect of dietary corn oil

Radioprotection of mouse skin by WR-2721: the critical influence of oxygen tension

International Nuclear Information System (INIS)

Denekamp, J.; Michael, B.D.; Rojas, A.; Stewart, F.A.

1982-01-01

The epidermal clone assay has been used to study the radioprotective effect of WR-2721 on mouse skin under different conditions of oxygenation and under anoxia. The skin has shown a progressive decrease in sensitivity as the inspired gas has changed from 100% oxygen towards 0% oxygen. Compared with mice breathning 100% oxygen, those breathing air are partially protected. The inspired oxygen concentration to give half the full oxygen effect is 10-12%. The radioprotecton observed with 400 mg/kg WR-2721 is markedly dependent on the ambient oxygen concentration. The protection factor is 1.1 or less in mice breathing 5%, 1% or 0% oxygen. Protection is maximal (1.95) in air and in 50% oxygen and diminishes to 1.6 at higher oxygen tensions

Effect of Artocarpus communis Extract on UVB Irradiation-Induced Oxidative Stress and Inflammation in Hairless Mice

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Feng-Lin Yen

2013-02-01

Full Text Available Administration of antioxidants and anti-inflammatory agents is an effective strategy for preventing ultraviolet (UV irradiation-induced skin damage. Artocarpus communis possesses several pharmacological activities, such as antioxidant, anticancer and anti-inflammation. However, the photoprotective activity of methanol extract of A. communis heartwood (ACM in ultraviolet irradiation-induced skin damage has not yet been investigated. The present study was performed using ultraviolet absorption, histopathological observation, antioxidant and anti-inflammation assays to elucidate the mechanism of the photoprotective activity of ACM. Our results indicated that ACM displayed a UVA and UVB absorption effect and then effectively decreased scaly skin, epidermis thickness and sunburn cells during ultraviolet irradiation in hairless mice. ACM not only decreased ultraviolet irradiation-mediated oxidative stress, including lowering the overproduction of reactive oxygen species and lipid peroxidation (p < 0.05, but also reduced the levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α and interleukin 1β. Additionally, ACM can decrease the synthesis of cytosolic phospholipase A2, cyclooxygenase, inducible nitric oxide synthase and vascular cell adhesion molecular-1 via inhibiting TNF-α-independent pathways (p < 0.05 in UVB-mediated inflammation and formation of sunburn cells. Consequently, we concluded that ACM extract has a photoprotective effect against UVB-induced oxidative stress and inflammation due to its sunscreen property, and its topical formulations may be developed as therapeutic and/or cosmetic products in further studies.

C/EBPalpha and C/EBPbeta are required for Sebocyte differentiation and stratified squamous differentiation in adult mouse skin.

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John S House

Full Text Available C/EBPalpha and C/EBPbeta are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPalpha and C/EBPbeta in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPalpha or C/EBPbeta alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPalpha and C/EBPbeta in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPalpha and C/EBPbeta in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3 and melanocortin 5 receptor (MC5R, two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPalpha and C/EBPbeta are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.

A novel vesicular carrier, transethosome, for enhanced skin delivery of voriconazole: characterization and in vitro/in vivo evaluation.

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Song, Chung Kil; Balakrishnan, Prabagar; Shim, Chang-Koo; Chung, Suk-Jae; Chong, Saeho; Kim, Dae-Duk

2012-04-01

This study describes a novel carrier, transethosome, for enhanced skin delivery of voriconazole. Transethosomes (TELs) are composed of phospholipid, ethanol, water and edge activator (surfactants) or permeation enhancer (oleic acid). Characterization of the TELs was based on results from recovery, particle size, transmission electron microscopy (TEM), zeta potential and elasticity studies. In addition, skin permeation profile was obtained using static vertical diffusion Franz cells and hairless mouse skin treated with TELs containing 0.3% (w/w) voriconazole, and compared with those of ethosomes (ELs), deformable liposomes (DLs), conventional liposomes (CLs) and control (polyethylene glycol, PG) solutions. The recovery of the studied vesicles was above 90% in all vesicles, as all of them contained ethanol (7-30%). There was no significant difference in the particles size of all vesicles. The TEM study revealed that the TELs were in irregular spherical shape, implying higher fluidity due to perturbed lipid bilayer compared to that of other vesicles which were of spherical shape. The zeta potential of vesicles containing sodium taurocholate or oleic acid showed higher negative value compared to other vesicles. The elasticities of ELs and TELs were much higher than that of CLs and DLs. Moreover, TELs dramatically enhanced the skin permeation of voriconazole compared to the control and other vesicles (p<0.05). Moreover, the TELs enhanced both in vitro and in vivo skin deposition of voriconazole in the dermis/epidermis region compared to DLs, CLs and control. Therefore, based on the current study, the novel carrier TELs could serve as an effective dermal delivery for voriconazole. Copyright © 2011 Elsevier B.V. All rights reserved.

Penetration of radionuclides across skin barriers of animal skin models in vitro

International Nuclear Information System (INIS)

Koprda, V.; Harangozo, M.; Bohacik, L.; Kassai, Z.

1998-01-01

In this paper: (i) the time dependence of permeation of 137 Cs + , 60 Co 2+ , and 147 Pm 3+ from aqueous solution through animal skin model has been studied, (ii) the biologic structure mostly responsible for the barrier effect was selected and proved, (iii) the relative importance of the main diffusion pathways for 137 Cs + , 60 Co 2+ and 147 Pm 3+ (the diffusion across the intact skin and the diffusion through the hair channels) was assessed. All experiments were done using radioactive tracers. Experimental arrangement consisted of Franz-type vertical permeation cells used with fresh skin from abdominal region of 5 day old rats (5DR) of Wistar strain (Breeding Farm Dobra Voda, SK) and 9 day old rats (9DR), respectively. 5DR are still hairless, and 9DR are just short haired. The 5DR skin was used in full form (intact), and then with decreasing thickness of horny layer after the skin had been stripped with Scotch type (3M) 5-20 times respectively, or the skin was splitted under 60 degC hot water so that the whole epidermis was removed. The penetrated amounts of ions were found to be proportional to the time at least in the first 7 hours. The permeation resistance of the skin is proportional to the thickness of the horny layer, the principal barrier mostly restricting the flux of ions. The more the skin is stripped, the more enhanced is the penetration of ions. This corroborates the fact that stratum corneum represents the most important barrier function of the whole skin (of rats). The additional diffusion through channels along hairs (follicules) can be of important value also in case of human skin where hair density is many times lower than in the case of the animal models used

Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis

International Nuclear Information System (INIS)

Webb, Meghan; Myal, Yvonne; Shiu, Robert; Murphy, Leigh C; Watson, Peter H; Emberley, Ethan D; Lizardo, Michael; Alowami, Salem; Qing, Gefei; Alfia'ar, Abdullah; Snell-Curtis, Linda J; Niu, Yulian; Civetta, Alberto

2005-01-01

The human psoriasin (S100A7) gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization) with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression

Hemin inhibits cyclooxygenase-2 expression through nuclear factor-kappa B activation and ornithine decarboxylase expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin

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Park, Jae Hee; Lee, Chang Ki [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Oral Cancer Research Institute, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Hwang, Young Sun [Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Park, Kwang-Kyun [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Chung, Won-Yoon [Department of Oral Biology, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of); Department of Applied Life Science and Brain Korea 21 Project, Yonsei University College of Dentistry, 134 Shinchon-Dong, Seodaemoon-Ku, Seoul 120-752 (Korea, Republic of)], E-mail: wychung@yuhs.ac

2008-07-03

Inflammation induced by various stimuli has been found to be associated with increased risk for most types of human cancer. Inflammation facilitates the initiation of normal cells, as well as the growth of initiated cells and their progression to malignancy through production of proinflammatory cytokines and diverse reactive oxygen/nitrogen species. These also activate the signaling molecules that are involved in inflammation and carcinogenesis. Our previous studies have demonstrated that hemin inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced bacterial mutagenesis and oxidative DNA damage, reduced the level of DNA-DMBA adduct and 12-O-tetradecanoylphorobl-13-acetate (TPA)-induced tumor formation in DMBA-initiated ICR mouse skin, and inhibited myeloperoxidase and ornithine decarboxylase (ODC) activity and H{sub 2}O{sub 2} formation in TPA-treated mouse skin. In the present study, to further elucidate the molecular mechanisms underlying the chemopreventive activity of hemin, its effect on the expression of ODC and cyclooxygenase (COX)-2, and the activation of nuclear factor-kappa B (NF-{kappa}B) and mitogen-activated protein kinases (MAPKs) regulating these proteins were explored in mouse skin with TPA-induced inflammation. Topically applied hemin inhibited ear edema and epidermal thickness in mice treated with TPA. Pretreatment with hemin reduced the expression of ODC and COX-2, and also reduced NF-{kappa}B activation in TPA-stimulated mouse skin. In addition, hemin suppressed the TPA-induced activation of extracellular signal-regulated protein kinase (ERK) and p38 MAPK in a dose-dependent manner. Taken together, hemin inhibited TPA-induced COX-2 expression by altering NF-{kappa}B signaling pathway via ERK and p38 MAPK, as well as TPA-induced ODC expression in mouse skin. Thereby, hemin may be an attractive candidate for a chemopreventive agent.

Hemin inhibits cyclooxygenase-2 expression through nuclear factor-kappa B activation and ornithine decarboxylase expression in 12-O-tetradecanoylphorbol-13-acetate-treated mouse skin

International Nuclear Information System (INIS)

Park, Jae Hee; Lee, Chang Ki; Hwang, Young Sun; Park, Kwang-Kyun; Chung, Won-Yoon

2008-01-01

Inflammation induced by various stimuli has been found to be associated with increased risk for most types of human cancer. Inflammation facilitates the initiation of normal cells, as well as the growth of initiated cells and their progression to malignancy through production of proinflammatory cytokines and diverse reactive oxygen/nitrogen species. These also activate the signaling molecules that are involved in inflammation and carcinogenesis. Our previous studies have demonstrated that hemin inhibited 7,12-dimethylbenz[a]anthracene (DMBA)-induced bacterial mutagenesis and oxidative DNA damage, reduced the level of DNA-DMBA adduct and 12-O-tetradecanoylphorobl-13-acetate (TPA)-induced tumor formation in DMBA-initiated ICR mouse skin, and inhibited myeloperoxidase and ornithine decarboxylase (ODC) activity and H 2 O 2 formation in TPA-treated mouse skin. In the present study, to further elucidate the molecular mechanisms underlying the chemopreventive activity of hemin, its effect on the expression of ODC and cyclooxygenase (COX)-2, and the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) regulating these proteins were explored in mouse skin with TPA-induced inflammation. Topically applied hemin inhibited ear edema and epidermal thickness in mice treated with TPA. Pretreatment with hemin reduced the expression of ODC and COX-2, and also reduced NF-κB activation in TPA-stimulated mouse skin. In addition, hemin suppressed the TPA-induced activation of extracellular signal-regulated protein kinase (ERK) and p38 MAPK in a dose-dependent manner. Taken together, hemin inhibited TPA-induced COX-2 expression by altering NF-κB signaling pathway via ERK and p38 MAPK, as well as TPA-induced ODC expression in mouse skin. Thereby, hemin may be an attractive candidate for a chemopreventive agent

Staphylococcus aureus penetrate the interkeratinocyte spaces created by skin-infiltrating neutrophils in a mouse model of impetigo.

Science.gov (United States)

Imanishi, Ichiro; Hattori, Shinpei; Hisatsune, Junzo; Ide, Kaori; Sugai, Motoyuki; Nishifuji, Koji

2017-02-01

Impetigo is a bacterial skin disease characterized by intraepidermal neutrophilic pustules. Previous studies have demonstrated that exfoliative toxin producing staphylococci are isolated in the cutaneous lesions of human and canine impetigo. However, the mechanisms of intraepidermal splitting in impetigo remain poorly understood. To determine how staphylococci penetrate the living epidermis and create intraepidermal pustules in vivo using a mouse model of impetigo. Three Staphylococcus aureus strains harbouring the etb gene and three et gene negative strains were epicutaneously inoculated onto tape-stripped mouse skin. The skin samples were subjected to time course histopathological and immunofluorescence analyses to detect intraepidermal neutrophils and infiltrating staphylococci. To determine the role of neutrophils on intraepidermal bacterial invasion, cyclophosphamide (CPA) was injected intraperitoneally into the mice to cause leucopenia before the inoculation of etb gene positive strains. In mice inoculated with etb gene positive S. aureus, intraepidermal pustules resembling impetigo were detected as early as 4 h post-inoculation (hpi). Neutrophils in the epidermis were detected from 4 hpi, whereas intraepidermal staphylococci was detected from 6 hpi. The dimensions of the intraepidermal clefts created in mice inoculated with etb gene positive strains at 6 hpi were significantly larger than those in mice inoculated with et gene negative strains. In CPA treated mice, staphylococci or neutrophils were not detected in the deep epidermis until 6 hpi. Our findings indicate that intraepidermal neutrophils play an important role in S. aureus invasion into the living epidermis in a mouse model of impetigo. © 2016 ESVD and ACVD.

Effect of synthetic vernix biofilms on barrier recovery of damaged mouse skin.

Science.gov (United States)

Oudshoorn, Marion H M; Rissmann, Robert; van der Coelen, Dennis; Hennink, Wim E; Ponec, Maria; Bouwstra, Joke A

2009-08-01

The aim of this work was to investigate whether topical application of synthetic biofilms supports and accelerates the recovery of the murine skin barrier, disrupted by sequential tape stripping. Therefore, various biofilms were applied topically on disrupted mouse skin to determine which formulation could improve barrier function, as was observed previously for the natural biofilm vernix caseosa (VC). The biofilms [i.e. particles (synthetic corneocytes) embedded in a synthetic lipid matrix] mimic closely the physicochemical properties and structure of VC. Various formulations were prepared using different particle:lipid ratios, particles with different initial water content and uncoated or lipid-coated particles. It was observed that application of all tested formulations improved the skin barrier recovery rate and reduced crust formation and epidermal hyperproliferation. However, only one of the biofilms [i.e. B1; composed of uncoated particles with 50% (w/w) initial water content and particle:lipid ratio of 2:1] mimicked the effects of native VC most closely. This indicates the importance of the presence of individual components, i.e. barrier lipids and water, as well as the ratio of these components. Consequently, these observations suggest the potential use of this biofilm treatment clinically.

Aloesin from Aloe vera accelerates skin wound healing by modulating MAPK/Rho and Smad signaling pathways in vitro and in vivo.

Science.gov (United States)

Wahedi, Hussain Mustatab; Jeong, Minsun; Chae, Jae Kyoung; Do, Seon Gil; Yoon, Hyeokjun; Kim, Sun Yeou

2017-05-15

Cutaneous wound healing is a complex process involving various regulatory factors at the molecular level. Aloe vera is widely used for cell rejuvenation, wound healing, and skin moisturizing. This study aimed to investigate the effects of aloesin from Aloe vera on cutaneous wound healing and mechanisms involved therein. This study consisted of both in vitro and in vivo experiments involving skin cell lines and mouse model to demonstrate the wound healing effects of aloesin by taking into account several parameters ranging from cultured cell migration to wound healing in mice. The activities of Smad signaling molecules (Smad2 and Smad3), MAPKs (ERK and JNK), and migration-related proteins (Cdc42, Rac1, and α-Pak) were assessed after aloesin treatment in cultured cells (1, 5 and 10µM) and mouse skin (0.1% and 0.5%). We also monitored macrophage recruitment, secretion of cytokines and growth factors, tissue development, and angiogenesis after aloesin treatment using IHC analysis and ELISAs. Aloesin increased cell migration via phosphorylation of Cdc42 and Rac1. Aloesin positively regulated the release of cytokines and growth factors (IL-1β, IL-6, TGF-β1 and TNF-α) from macrophages (RAW264.7) and enhanced angiogenesis in endothelial cells (HUVECs). Aloesin treatment accelerated wound closure rates in hairless mice by inducing angiogenesis, collagen deposition and granulation tissue formation. More importantly, aloesin treatment resulted in the activation of Smad and MAPK signaling proteins that are key players in cell migration, angiogenesis and tissue development. Aloesin ameliorates each phase of the wound healing process including inflammation, proliferation and remodeling through MAPK/Rho and Smad signaling pathways. These findings indicate that aloesin has the therapeutic potential for treating cutaneous wounds. Copyright © 2017 Elsevier GmbH. All rights reserved.

Effects of whole-body and partial-body x irradiation upon epidermal mitotic activity during wound healing in mouse skin

International Nuclear Information System (INIS)

Kobayashi, K.

1977-01-01

Mitotic activity of normal (unwounded) and wounded skin was measured in the control (nonirradiated) and whole-body or partial-body x-irradiated mouse. Higher mitotic activity in the anterior than in the posterior region of the body was found in both the normal and the wounded skin of the control mouse. Whole-body irradiation (500 R) depressed completely the mitotic activity of normal skin 2 to 4 days after irradiation. In spite of this depression in mitotic activity, a surgical incision made 1 to 3 days after irradiation could induce a burst of proliferation after an inhibition of an initial mitosis increase. When the animals were partially irradiated with 500 R 3 days before wounding, it was shown that mitosis at 24 hr after wounding was inhibited markedly by the local effect of irradiation and that mitosis also could be inhibited diversely by the abscopal effect of irradiation. Because of a close similarity of sequential mitotic patterns between whole-body-irradiated and flapped-skin-only-irradiated groups (direct irradiation), the effect of irradiation upon mitosis was considered to be primarily local. Some discussions were made concerning the possible reasons which made a difference in mitotic patterns between the head-only-irradiated group, the irradiated group including the head and other parts of the body except for the skin flap

Effect of infrared radiation A on photoaged hairless mice harboring eumelanin and pheomelanin in the epidermis.

Science.gov (United States)

Okazaki, Shizuka; Funasaka, Yoko; Wakamatsu, Kazumasa; Kawana, Seiji; Saeki, Hidehisa

2015-04-01

Infrared radiation A (IRA) is absorbed by melanin and generates heat. Therefore, the effect of IRA could be well analyzed using skin, which contains melanin in the epidermis. Hairless mice harboring epidermal melanocytes that produce eumelanin, pheomelanin, or non-melanin were generated by backcrossing K14-stem cell factor mice, recessive yellow mice, and then albino hairless mice. High-dose IRA was irradiated over 18 weeks after the establishment of photoaged mice by irradiation with ultraviolet B (UVB) three times a week for 14 weeks. Tumor formation was assessed every week. The formation of cyclobutane pyrimidine dimer and apoptotic cells by the irradiation of IRA and UVB was evaluated. Repetitive irradiation of IRA did not promote tumor formation in all types of mice. Pre-irradiation of IRA to UVB, but not post-irradiation, accelerated the elimination of cyclobutane pyrimidine dimers and enhanced apoptosis; these effects were most obvious in eumelanin-producing mice. Real-time polymerase chain reaction analysis showed downregulation of FLICE (cellular caspase 8)-like inhibitory protein and B-cell lymphoma-extra large and upregulation of Bcl-2-associated X protein by UVB, but further enhancement of these molecules by pre-irradiation of IRA was not observed. These results indicate that IRA does not confer the promotion of UVB-induced carcinogenesis in photoaged mice harboring epidermal melanocytes and that photochemical reaction between IRA and melanin might be involved in the induction of apoptosis and the elimination of cyclobutane pyrimidine dimers by UVB. The enhancement of apoptosis by pre-irradiation of IRA to UVB might be induced by mechanisms other than the modification of the mRNA expression of FLICE (cellular caspase 8)-like inhibitory protein, B-cell lymphoma-extra large, and Bcl-2-associated X. © 2015 Japanese Dermatological Association.

Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard

Energy Technology Data Exchange (ETDEWEB)

Chang, Yoke-Chen; Wang, James D.; Hahn, Rita A.; Gordon, Marion K.; Joseph, Laurie B. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Heck, Diane E. [Department of Environmental Science, New York Medical College, Valhalla, NY (United States); Heindel, Ned D. [Department of Chemistry, Lehigh University, Bethlehem, PA (United States); Young, Sherri C. [Department of Chemistry, Muhlenberg College, Allentown, PA (United States); Sinko, Patrick J. [Department of Pharmaceutics, Rutgers University, Piscataway, NJ (United States); Casillas, Robert P. [MRIGlobal, Kansas City, MO (United States); Laskin, Jeffrey D. [Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States); Gerecke, Donald R., E-mail: gerecke@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ (United States)

2014-10-15

Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 h post-SM exposure. After 96 h, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermal–epidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure. - Highlights: • Bifunctional anti-inflammatory prodrug (NDH4338) tested on SM exposed mouse skin • The prodrug NDH4338 was designed to target COX2 and acetylcholinesterase. • The application of NDH4338 improved cutaneous wound repair after SM induced injury. • NDH4338 treatment demonstrated a reduction in COX2 expression on SM injured skin. • Changes of skin repair

The response of previously irradiated mouse skin to heat alone or combined with irradiation: influence of thermotolerance

International Nuclear Information System (INIS)

Wondergem, J.; Haveman, J.

1983-01-01

The effect of previous x-irradiation on the response to hyperthermia (44 0 C), x-irradiation, and irradiation combined with hyperthermia (43 0 C or 44 0 C) was studied in mouse foot skin. Irradiation of mice feet 90 days before, with 20 Gy, increased the subsequent response to heat alone, or combined with irradiation, as well as to irradiation alone. It had little effect on the thermal enhancement ratios for both acute and late skin reactions. Memory of the previous irradiation treatment could be masked when the temperature of the subsequent heat treatment alone, or combined with irradiation, was 44 0 C. Priming heat treatment induced resistance to a subsequent heat treatment and to a subsequent combined irradiation-heat treatment in normal as well as previously irradiated skin. When late skin reaction was considered, a larger 'memory' of the previous irradiation treatment was always evident, compared to acute skin reaction: the 'remembered' dose in the late skin reaction was about twice the 'remembered' dose in the acute reaction. (U.K.)

UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation.

Science.gov (United States)

Han, Mira; Ban, Jae-Jun; Bae, Jung-Soo; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-11-14

The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down-regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation.

Molecular Insights into SIRT1 Protection Against UVB-Induced Skin Fibroblast Senescence by Suppression of Oxidative Stress and p53 Acetylation.

Science.gov (United States)

Chung, Ki Wung; Choi, Yeon Ja; Park, Min Hi; Jang, Eun Ji; Kim, Dae Hyun; Park, Byung Hyun; Yu, Byung Pal; Chung, Hae Young

2015-08-01

Stresses, such as exposure to ultraviolet radiation and those associated with aging, are known to cause premature cellular senescence that is characterized by growth arrest and morphological and gene expression changes. This study was designed to investigate the protective effect of Sirtuin1 (SIRT1) on the UVB-induced premature senescence. Under in vitro experimental conditions, exposure to a subcytotoxic dose of UVB enhanced human skin fibroblasts senescence, as characterized by increased β-galactosidase activity and increased levels of senescence-associated proteins. However, adenovirus-mediated SIRT1 overexpression significantly protected fibroblasts from UVB-induced cellular deterioration. Exposure to UVB-induced cell senescence was associated with oxidative stress and p38 mitogen-activated protein kinase activation. Molecular analysis demonstrated that deacetylation of Forkhead box O3α (FOXO3α) by SIRT1 changed the transcriptional activity of FOXO3α and increased resistance to the oxidative stress. In addition, SIRT1 suppressed UVB-induced p53 acetylation and its transcriptional activity, which directly affected the cell cycle arrest induced by UVB. Further study demonstrated that SIRT1 activation inhibited cell senescence in the skin of the HR1 hairless mouse exposed to UVB. The study identifies a new role for SIRT1 in the UVB-induced senescence of skin fibroblats and provides a potential target for skin protection through molecuar insights into the mechanisms responsible for UVB-induced photoaging. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Mueller matrix polarimetry for characterizing microstructural variation of nude mouse skin during tissue optical clearing.

Science.gov (United States)

Chen, Dongsheng; Zeng, Nan; Xie, Qiaolin; He, Honghui; Tuchin, Valery V; Ma, Hui

2017-08-01

We investigate the polarization features corresponding to changes in the microstructure of nude mouse skin during immersion in a glycerol solution. By comparing the Mueller matrix imaging experiments and Monte Carlo simulations, we examine in detail how the Mueller matrix elements vary with the immersion time. The results indicate that the polarization features represented by Mueller matrix elements m22&m33&m44 and the absolute values of m34&m43 are sensitive to the immersion time. To gain a deeper insight on how the microstructures of the skin vary during the tissue optical clearing (TOC), we set up a sphere-cylinder birefringence model (SCBM) of the skin and carry on simulations corresponding to different TOC mechanisms. The good agreement between the experimental and simulated results confirm that Mueller matrix imaging combined with Monte Carlo simulation is potentially a powerful tool for revealing microscopic features of biological tissues.

Phenotypic and genetic characterization of a novel phenotype in pigs characterized by juvenile hairlessness and age dependent emphysema

DEFF Research Database (Denmark)

Bruun, Camilla S.; Jørgensen, Claus B.; Bay, Lene

2008-01-01

Background: A pig phenotype characterized by juvenile hairlessness, thin skin and age dependent lung emphysema has been discovered in a Danish pig herd. The trait shows autosomal co-dominant inheritance with all three genotypes distinguishable. Since the phenotype shows resemblance to the integrin...... of musculi arrectores pili, and at puberty or later localized areas of emphysema are seen in the lungs. Comparative mapping predicted that the porcine ITGB6 and ITGAV orthologs map to SSC15. In an experimentall family (n=113), showing segregation of the trait, the candidate region was confirmed by linkage...... splicing of the ITGB6 pre-mRNA was detected. For both ITGB6 and ITGAV quantitative PCR revealed no significant difference in the expression levels in normal and affected animals. In a western blot, ITGB6 was detected in lung protein samples of all three genotypes. This result was supported by flow...

Mouse skin damages caused by fractionated irradiation with carbon ions

International Nuclear Information System (INIS)

Ando, K.; Chen, Y.J.; Ohira, C.; Nojima, K.; Ando, S.; Kobayashi, N.; Ohbuchi, T.; Shimizu, W.; Koike, S.; Kanai, T.

1997-01-01

We have investigated carbon-dose responses of early and late skin damages after daily fractionations to the mouse leg. Depilated legs were irradiated with 7 different positions within 290 MeV/u carbon beams. Fractionation schedules were 1, 2, 4 and 8 daily fractions. Skin reaction was scored every other day for 32 days. Five highest scores in individual mice were averaged, and used as averaged peak reaction. The isoeffect doses to produce an averaged peak skin reaction of 3.0 (moist desquamation) on dose-response curves were calculated with 95% confidence limit. The isoeffect dose for control gamma rays constantly increased with an increase in the number of fraction. The isoeffect doses in low LET carbon ions of 14- and 20 keV/μm also increased up to 4 fractions, but did not increase when 4 fractions increased to 8 fractions. The saturation of isoeffect dose was more prominently observed for 40 keV/μm in such that the isoeffect doses did not change among 2, 4 and 8 fractions. The isoeffect doses for LET higher than 50 keV/μm were smaller than those for lower LET. However, the isoeffect doses for 50-, 60-, 80- and 100 keV/μ steadily increased with an increase in the number of fraction and did not show any saturation up to 8 fractions. Relation between LET and RBE was linear for all fractionation schedules. The slope of regression line in 4 fractions was steepest, and significantly (P<0.05) different from that in 1 fraction. (orig.)

Mouse skin damages caused by fractionated irradiation with carbon ions

Energy Technology Data Exchange (ETDEWEB)

Ando, K; Chen, Y J; Ohira, C; Nojima, K; Ando, S; Kobayashi, N; Ohbuchi, T; Shimizu, W [Space and Particle Radiation Science Research Group, Chiba (Japan); Koike, S; Kanai, T [National Inst. of Radiological Sciences, Chiba (Japan). Div. of Accelerator Physics

1997-09-01

We have investigated carbon-dose responses of early and late skin damages after daily fractionations to the mouse leg. Depilated legs were irradiated with 7 different positions within 290 MeV/u carbon beams. Fractionation schedules were 1, 2, 4 and 8 daily fractions. Skin reaction was scored every other day for 32 days. Five highest scores in individual mice were averaged, and used as averaged peak reaction. The isoeffect doses to produce an averaged peak skin reaction of 3.0 (moist desquamation) on dose-response curves were calculated with 95% confidence limit. The isoeffect dose for control gamma rays constantly increased with an increase in the number of fraction. The isoeffect doses in low LET carbon ions of 14- and 20 keV/{mu}m also increased up to 4 fractions, but did not increase when 4 fractions increased to 8 fractions. The saturation of isoeffect dose was more prominently observed for 40 keV/{mu}m in such that the isoeffect doses did not change among 2, 4 and 8 fractions. The isoeffect doses for LET higher than 50 keV/{mu}m were smaller than those for lower LET. However, the isoeffect doses for 50-, 60-, 80- and 100 keV/{mu} steadily increased with an increase in the number of fraction and did not show any saturation up to 8 fractions. Relation between LET and RBE was linear for all fractionation schedules. The slope of regression line in 4 fractions was steepest, and significantly (P<0.05) different from that in 1 fraction. (orig.)

Effect of BCNU on mouse skin and spinal cord in single drug and radiation exposures

International Nuclear Information System (INIS)

Lelieveld, P.; Brown, J.M.; Goffinet, D.R.; Schoeppel, S.L.; Scoles, M.

1979-01-01

We set out to determine whether any interaction occurs between BCNU and radiation for the mouse skin and spinal cord. Single doses of BCNU of 10, 20, or 30 mg/kg were injected intraperitoneally as a function of time before or after irradiation of the foot or spinal cord of anesthesized C3H mice. Enhancement of the radiation skin reaction (dose enhancement factor = 1.3) was seen when BCNU (30 mg/kg) was given 1 day, 6 hr, and 2 hr prior to irradiation of the foot with 2,500 rad, and a larger DEF of 1.6 was observed when BCNU was given immediately before the radiation dose. However, with a different mouse strain (BALB/c) not anesthetized at the time of irradiation, no significant enhancement following a dose of 20 mg/kg BCNU was observed. Experiments are in progress to determine the cause of these differences. BCNU (10 mg/kg) was given 24 hr or immediately prior to various single doses of radiation to a 12 mm segment of the mouse spinal cord (T/sub 11-12/ to L/sub 1-2/), and the subsequent myelitis was scored monthly. The addition of BCNU to irradiation did not accelerate the development of myelitis, not the ultimate proportion of animals developing hind limb paralysis: the 50% myelitis dose at 10 months (MD/sub 50/10/sub mo/) values for irradiation alone, BCNU at the time of irradiation and 24 hr before were 3,722, 3,795 and 3,853 rad, respectively

Whorled hairless nevus of the scalp, linear hyperpigmentation, and telangiectatic nevi of the lower limbs: a novel variant of the "phacomatosis complex".

Science.gov (United States)

Castori, Marco; Scarciolla, Oronzo; Morlino, Silvia; Manente, Liborio; Biscaglia, Assunta; Fragasso, Alberto; Grammatico, Paola

2012-02-01

The term "phacomatosis" refers to a growing number of sporadic genetic skin disorders characterized by the combination of two or more different nevi and possibly resulting from non-allelic twin spotting. While phacomatosis pigmentovascularis (PPV) and pigmentokeratotica represent the most common patterns, some patients do not fit with either condition and are temporarily classified as unique phenotypes. We report on an 8-year-old boy with striking right hemihypoplasia, resulting in limb asymmetry and fixed dislocation of right hip. Skin on the affected side showed three distinct nevi: (i) A whorled, hairless nevus of the scalp in close proximity with (ii) epidermal hyperpigmentation following lines of Blaschko on the neck and right upper limb, and (iii) multiple telangiectatic nevi of the right lower limb and hemiscrotum. Didymosis atricho-melanotica was proposed for the combination of adjacent patchy congenital alopecia and linear hyperpigmentation, while phacomatosis atricho-pigmento-vascularis appears to define the entire cutaneous phenotype, thus implying the involvement of three neighboring loci influencing the development of distinct constituents of the skin. Given the striking asymmetry of the observed phenotype, the effect of mosaicism (either genomic or functional) for a mutation in a single gene with pleiotropic action and influenced by the lateralization pattern of early development cannot be excluded. Copyright © 2012 Wiley Periodicals, Inc.

The measurement of skin impedance for the diagnosis of skin cancer

International Nuclear Information System (INIS)

Menzies, S.; Crook, B.; McCarthy, W.

1996-01-01

Full text: In vivo skin impedance measurements have been reported to be diagnostic in differentiating benign from malignant skin tumours (Kiss G et al. Borgyogy Vener Szle 45: 164,1969; Melczer N. In: Cancer of the Skin. Saunders Co. Philadelphia, 1976, pp293-313). However, in contrast to non-melanoma skin cancer, only, a small sample of malignant melanomas were reported in these previous studies. We performed skin impedance measurements on a larger sample of melanomas in order to assess the potential use of such instrumentation for clinical diagnosis. The diagnostic method described by Kiss and Horvath was reproduced with only minor modifications. Low voltage impedance measurements at 1600 Hz were taken over each lesion and on nearby surrounding normal skin. Filter paper (4mm diameter) soaked in 0.1 M KCl was used at the skin-probe interface. A minimum of 2 skin and 1 lesion measurements were taken. All lesions were taken from relatively hairless sites and were non abraded or ulcerated. With the exception of 6 seborrhoeic keratoses all lesions were excised for histological diagnosis. The lesions tested were 27 invasive melanomas, 3 in situ melanomas, 27 basal cell carcinomas (BCC), 70 benign melanocytic lesions, 19 seborrhoeic keratoses, 5 Bowens disease (in situ SCC), 1 squamous cell carcinoma (SCC) and 25 other benign lesions. Results were interpreted as previously (Melczer) by the quotient of skin impedance / lesion impedance > 1.5 indicating malignancy. Analysis of total melanocytic lesions gave a sensitivity of 44% and specificity of 83% for the diagnosis of invasive melanoma (p < 0.05). Fifty two percent of BCCs were positively diagnosed. Analysis of all benign versus all invasive malignancy gave a sensitivity of 47% and specificity of 77% for the diagnosis of invasive malignancy (p < 0.01). While impedance measurements at 1600 Hz provide a statistically significant differentiation of melanoma versus non-melanoma and invasive malignancy versus benign lesions

A review of electroporation-based antitumor skin therapies and investigation of betulinic acid-loaded ointment.

Science.gov (United States)

Bakonyi, Monika; Berko, Szilvia; Eros, Gabor; Varju, Gabor; Dehelean, Cristina; Szucs, Maria Budai; Csanyi, Erzsebet

2017-11-13

Electrochemotherapy is a novel treatment for cutaneous and subcutaneous tumors utilizing the combination of electroporation and chemotherapeutic agents. Since tumors have an increasing incidence nowadays as a result of environmental and genetic factors, electrochemotherapy could be a promising treatment for cancer patients. The aim of this article is to summarize the novel knowledge about the use of electroporation for antitumor treatments and to present a new application of electrochemotherapy with a well-known plant derived antitumor drug betulinic acid. For the review we have searched the databases of scientific and medical research to collect the available publications about the use of electrochemotherapy in the treatment of various types of cancer. By the utilization of the available knowledge, we investigated the effect of electroporation on the penetration of a topically applied betulinic acid formulation into the skin by ex vivo Raman spectroscopy on hairless mouse skin Results: Raman measurements have demonstrated that the penetration depth of betulinic acid can be remarkably ameliorated by the use of electroporation, so this protocol can be a possibility for the treatment of deeper localized cancer nodules. Furthermore, it proved the influence of various treatment times, since they caused different spatial distributions of the drug in the skin. The review demonstrates that electrochemotherapy is a promising tool to treat different kinds of tumors with high efficiency and with only a few moderate adverse effects. Moreover, it presents a non-invasive method to enhance the penetration of antitumor agents, which can offer novel prospects for antitumor therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

INHIBITION OF THE DNA-BINDING ACTIVITY OF DROSOPHILA SUPPRESSOR OF HAIRLESS AND OF ITS HUMAN HOMOLOG, KBF2/RBP-J-KAPPA, BY DIRECT PROTEIN-PROTEIN INTERACTION WITH DROSOPHILA HAIRLESS

NARCIS (Netherlands)

BROU, C; LOGEAT, F; LECOURTOIS, M; VANDEKERCKHOVE, Joël; KOURILSKY, P; SCHWEISGUTH, F; ISRAEL, A

1994-01-01

We have purified the sequence-specific DNA-binding protein KBF2 and cloned the corresponding cDNA, which is derived from the previously described RBP-J kappa gene, the human homolog of the Drosophila Suppressor of Hairless [Su(H)] gene. Deletion studies of the RBP-J kappa and Su(H) proteins allowed

The epidermal cell kinetic response to ultraviolet B irradiation combines regenerative proliferation and carcinogen associated cell cycle delay

Energy Technology Data Exchange (ETDEWEB)

Olsen, W.M.; Kirkhus, B. (Oslo Univ. (Norway))

1989-09-01

The cell cycle traverse of epidermal basal cells 24 h after in vivo exposure of ultraviolet B (UVB) irradiation was studied by immunochemical staining of incorporated bromodeoxyuridine (BrdU) and bivariate BrdU/DNA flow cytometric analysis. The results were compared with the cell kinetic patterns following topical application of the skin carcinogen methylnitrosourea (MNU) as well as the skin irritant cantharidin. The cell cycle traverse in hairless mouse epidermis 24 h after in vivo exposure to UVB seemed to be a combination of the cell kinetic effects following chemical skin carcinogens and skin irritants. UVB irradiation induced both a delay in transit time through S phase, probably due to DNA damage and subsequent repair, as well as a reduction in the total cell cycle time consistent with rapid regenerative proliferation. (author).

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

Science.gov (United States)

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

Ionizing Radiation Affects Gene Expression in Mouse Skin and Bone

Science.gov (United States)

Terada, Masahiro; Tahimic, Candice; Sowa, Marianne B.; Schreurs, Ann-Sofie; Shirazi-Fard, Yasaman; Alwood, Joshua; Globus, Ruth K.

2017-01-01

Future long-duration space exploration beyond low earth orbit will increase human exposure to space radiation and microgravity conditions as well as associated risks to skeletal health. In animal studies, radiation exposure (greater than 1 Gy) is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Definitive measurements and detection of bone loss typically require large and specialized equipment which can make their application to long duration space missions logistically challenging. Towards the goal of developing non-invasive and less complicated monitoring methods to predict astronauts' health during spaceflight, we examined whether radiation induced gene expression changes in skin may be predictive of the responses of skeletal tissue to radiation exposure. We examined oxidative stress and growth arrest pathways in mouse skin and long bones by measuring gene expression levels via quantitative polymerase chain reaction (qPCR) after exposure to total body irradiation (IR). To investigate the effects of irradiation on gene expression, we used skin and femora (cortical shaft) from the following treatment groups: control (normally loaded, sham-irradiated), and IR (0.5 Gy 56Fe 600 MeV/n and 0.5 Gy 1H 150 MeV/n), euthanized at one and 11 days post-irradiation (IR). To determine the extent of bone loss, tibiae were harvested and cancellous microarchitecture in the proximal tibia quantified ex vivo using microcomputed tomography (microCT). Statistical analysis was performed using Student's t-test. At one day post-IR, expression of FGF18 in skin was significantly greater (3.8X) than sham-irradiated controls, but did not differ at 11 days post IR. Expression levels of other genes associated with antioxidant response (Nfe2l2, FoxO3 and Sod1) and the cell cycle (Trp53, Cdkn1a, Gadd45g) did not significantly differ between the control and IR groups

A study of nutrient digestibility and growth performance of broiler chicks fed hairy and hairless canary seed (Phalaris canariensis L.) products.

Science.gov (United States)

Newkirk, R W; Ram, J I; Hucl, P; Patterson, C A; Classen, H L

2011-12-01

A nutrient retention study and a growth study were conducted with broiler chickens to evaluate the nutritive value and potential toxicity of 2 hairless canary seed products-hulled seed and groats (cultivar CDC Maria), and one hairy hulled canary seed (cultivar Keet). Each treatment was replicated 6 times (6 groups of 4 birds each). The hairless canary seed groat, hairless hulled canary seed, and the hairy hulled canary seed contained 24.5, 21.8, and 16.3% CP; 7.1, 5.8, and 6.6% ether extract; 1.5, 14.2, and 12.3% acid detergent fiber, and 3,867, 3,205 and 3,292 kcal/kg of AME(n), on a DM basis, respectively. The hairless canary seed groat, hairless hulled canary seed, and the hairy hulled canary seed protein comprised, respectively, 0.49, 0.33, and 0.33% lysine (DM basis), which was 79, 78, and 67% digestible (apparent ileal); 0.65, 0.53, and 0.60% cysteine (DM basis), which was 86, 87, and 85% apparent ileal digestible; and 0.40, 0.30, and 0.25% methionine (DM basis), which was 89, 90, and 86% apparent ileal digestible. In the second study, a 35-d feeding study with male broiler chickens was conducted. The canary seed products were compared with a Canadian Western Red Spring wheat control. Each treatment was replicated 6 times (6 groups of 4 birds each). The test ingredients comprised 50% of the corn/soybean diets. The birds fed the hulled canary seed (hairy or hairless) had similar weight gain, feed intake, and G:F to those fed wheat. There were no statistically significant (P = 0.05) differences in the weights of the bursa, heart, kidneys, liver, spleen, or the pancreas, nor was there any effect on serum lactate dehydrogenase or creatine kinase. The data indicated that feeding hulled canary seed increased the number of gizzard ulcers (P < 0.01). It was concluded that canary seed does not contain anti-nutritional components that negatively affect broiler performance or bird health. However, the canary seed hulls may damage the gizzard lining.

Chronic UVA (365-nm) irradiation induced scratching in hairless mice: dose-time dependency and the effect of ketanserin

International Nuclear Information System (INIS)

Laat, J.M.T. de; Groenendijk, M.; Vloten, W.A. van; Gruijl, F.R. de; Seite, S.

1997-01-01

In a study on the dose-response relationship for longwave UVA (UVA1; 340-400 nm) carcinogenesis in hairless mice scratch marks appeared after months of daily exposure as an unwanted side effect. Tumor induction in the highest of the 4 tested dose groups (receiving a daily dose of 430 kJ/m 2 of 365-nm radiation) could not be determined because extensive scarification occurred prior to the development of any tumors. The induction of scratch marks could be scored and quantified in all 4 dose groups tested. The UVA1 dose-dependencies for the induction of tumors and scratch marks were compared. We found that the induction of scratch marks depended mainly on the cumulative UVA1 exposure, whereas tumor induction showed a lesser dose-dependency. An attempt was made to prevent the apparent pruritogenic effect of UVA1 irradiation and to understand its mechanism. The influence of ketanserin, a serotonin/histamine antagonist, on the UVA1 induction of scratch marks was tested in groups of 8 mice daily irradiated with 430 kJ/m 2 . No difference was found between treated and untreated animals. Histological examination of skin biopsies from irradiated mice from the 430-kJ/m 2 dose group from the UVA1 carcinogenic experiment, showed no changes in numbers of mast cells or other inflammatory features when compared to skin biopsies from unirradiated control mice. This indicated that UVA1-induced scratching is not mediated through mast cell release of serotonin and/or histamine. An adequate therapeutic treatment which can prevent UVA1-induced scratching would enable us to test tumor induction with UVA1 over a larger dose range, and may provide additional insight in how this radiation damages the skin. It remains conjectural whether there exists and analogous UVA-induced pruritus in human skin. (au)

Recovery of aging-related size increase of skin epithelial cells: in vivo mouse and in vitro human study.

Directory of Open Access Journals (Sweden)

Igor Sokolov

Full Text Available 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.

Photocarcinogenesis and persistent hyperplasia in UV-irradiated SENCAR mouse skin

International Nuclear Information System (INIS)

Strickland, P.T.

1986-01-01

Susceptibility to photocarcinogenesis has been examined in several mouse strains and stocks including SENCAR, CD-1, BALB/c, C3H, C57Bl, and NZB. SENCAR mice are hypersusceptible to tumorigenesis caused by single high dose exposures to ultraviolet (UV) radiation but not by chronic low-dose exposures. SENCAR mice also exhibit an exaggerated and persistent epidermal hyperplasia in response to UV-induced tissue damage. The persistent hyperplasia is apparently due to a sustained proliferation of the epithelial basal cells, rather than to delayed cell differentiation. SENCAR mice did not exhibit persistent hyperplasia following other forms of tissue damage (surgical or thermal). In related studies, the levels of thymine dimers induced in SENCAR epidermis by UV radiation were comparable to those observed in BALB/c epidermis. In addition, no differences were found in the tissue distribution or persistence of thymine dimers in SENCAR and BALB/c skin

Application of BALB/c mouse in the local lymph node assay:BrdU-ELISA for the prediction of the skin sensitizing potential of chemicals.

Science.gov (United States)

Hou, Fenxia; Xing, Caihong; Li, Bin; Cheng, Juan; Chen, Wei; Zhang, Man

2015-01-01

Allergic contact dermatitis (ACD) is a skin disease characterized by eczema and itching. A considerable proportion of chemicals induce ACD in humans. More than 10,000 substances should be tested for skin sensitization potential under the Registration, Evaluation, Authorization and Restriction of Chemical substances (REACH) regulation. The Local Lymph Node Assay (LLNA) has been designated as the first-choice in vivo assay for sensitization testing by REACH. The LLNA:BrdU-ELISA is a validated non-radioactive modification to the LLNA. For both the LLNA and the LLNA:BrdU-ELISA, CBA/JN mouse is the preferred mouse strain recommended in the regulatory guidelines. However, the availability of CBA/JN mouse in China is only limited to a few animal suppliers, which makes the mouse difficult to obtain. BALB/c mouse, which is widely commercially available, is considered for alternative use but it can only be used in the assay after it has been evaluated by formal validation study. Thus, a validation study was conducted in our laboratory to determine if BALB/c mouse could also be used in the LLNA:BrdU-ELISA. Forty-three test substances including 32 LLNA sensitizers and 11 LLNA non-sensitizers, their vehicles and each concentration used were the same as that used in the formal validation study for the LLNA:BrdU-ELISA using CBA/JN mouse. Female BALB/c mice of 8-10 weeks old were randomly allocated to groups (four mice per group). The test substance (25 μl) or the vehicle alone was applied to the dorsum of both ears daily for 3 consecutive days. A single intraperitoneal injection of 0.5 ml of BrdU (10mg/ml) solution was given on day 5. On day 6, a pair of auricular lymph nodes from each mouse was excised, weighed and stored at -20°C until BrdU-ELISA was conducted. This validation study for the LLNA:BrdU-ELISA using BALB/c mouse correctly identified 30 of 31 sensitizers and 8 of 11 non-sensitizers. The accuracy, sensitivity, specificity, false positive rate, false negative rate

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

Energy Technology Data Exchange (ETDEWEB)

Boulware, Stephen [Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723 (United States); Fields, Tammy; McIvor, Elizabeth; Powell, K. Leslie; Abel, Erika L. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957 (United States); Vasquez, Karen M. [Division of Pharmacy and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Blvd., Austin, TX 78723 (United States); MacLeod, Michael C., E-mail: mcmacleod@mdanderson.org [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957 (United States)

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.

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

International Nuclear Information System (INIS)

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

2012-01-01

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.

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

International Nuclear Information System (INIS)

Gopee, Neera V.; Cui, Yanyan; Olson, Greg; Warbritton, Alan R.; Miller, Barbara J.; Couch, Letha H.; Wamer, Wayne G.; Howard, Paul C.

2005-01-01

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

Quantitative Methods for Measuring Repair Rates and Innate-Immune Cell Responses in Wounded Mouse Skin.

Science.gov (United States)

Li, Zhi; Gothard, Elizabeth; Coles, Mark C; Ambler, Carrie A

2018-01-01

In skin wounds, innate-immune cells clear up tissue debris and microbial contamination, and also secrete cytokines and other growth factors that impact repair process such as re-epithelialization and wound closure. After injury, there is a rapid influx and efflux of immune cells at wound sites, yet the function of each innate cell population in skin repair is still under investigation. Flow cytometry is a valuable research tool for detecting and quantifying immune cells; however, in mouse back skin, the difficulty in extracting immune cells from small area of skin due to tissue complexity has made cytometric analysis an underutilized tool. In this paper, we provide detailed methods on the digestion of lesion-specific skin without disrupting antigen expression followed by multiplex cell staining that allows for identification of seven innate-immune populations, including rare subsets such as group-3 innate lymphoid cells (ILC3s), by flow-cytometry analysis. Furthermore, when studying the functions of immune cells to tissue repair an important metric to monitor is size of the wound opening. Normal wounds close steadily albeit at non-linear rates, while slow or stalled wound closure can indicate an underlying problem with the repair process. Calliper measurements are difficult and time-consuming to obtain and can require repeated sedation of experimental animals. We provide advanced methods for measuring of wound openness; digital 3D image capture and semi-automated image processing that allows for unbiased, reliable measurements that can be taken repeatedly over time.

UVA-induced mutational spectra in the laci gene from transgenic mouse skin

International Nuclear Information System (INIS)

Gorelick, N.J.; O'Kelly, J.A.; Biedermann, K.A.

1995-01-01

The UVB (295-320 nm) component of sunlight was once thought to be the sole cause of photoaging and skin cancer. However, there is now compelling evidence to suggest that chronic irradiation with UVA (320-400 nm) is a significant component of the etiologies of these diseases. To identify acute markers of UVA damage, we investigated UVA-induced mutagenesis in vivo by using a lacI transgenic mouse mutation assay. The backs of adult female C57BL/6 Big Blue reg-sign mice were shaved and exposed daily to a low or a high dose of UVA for 5 consecutive days. One group remained unexposed. The high dose of UVA significantly increased the mutant frequency in skin determined 12 days after the last exposure. Mutant frequencies were (Avg ± SEM, n=7-8/group): 6.1 ± 0.5 x 10 -5 (high dose). DNA sequence analysis of mutant lacI genes demonstrated that the high dose of UVA produced a different mutational spectrum compared to control. The mutational spectrum from the low dose mutants was not different from the control spectrum in skin generated previously; the predominant classes of recovered mutations were GC→At transitions at CpG sites (11/35) and GC →TA transversions (12/35). In contrast, in the high dose group, GC →AT transitions at non-CpG sites predominated (61/97 mutations); three tandem base substitutions (1 GG →AA; 2 CC→TT) were uniquely recovered; and an increased frequency of recovered GC→CG substitutions was observed (12/97 vs. none in controls). The recovered high dose spectrum is consistent with the types of DNA damage generated by UVA as well as by reactive oxygen species. These studies demonstrate that UVA is mutagenic in vivo and that this assay can be used to study early events in UVA-induced skin damage

UVB-induced epidermal hyperproliferation is modified by a single, topical treatment with a mitosis inhibitory epidermal pentapeptide

International Nuclear Information System (INIS)

Olsen, W.M.; Elgjo, K.

1990-01-01

A single application of a water-miscible cream base containing the recently identified mitosis inhibitory epidermal pentapeptide pyroGlu-Glu-Asp-Ser-GlyOH (EPP) to hairless mouse skin is followed by a long-lasting period of reduced epidermal cell proliferation. To examine if a similar growth inhibition could be achieved in stimulated and rapidly proliferating epidermis, EPP was applied at two different concentrations, 0.005 or 0.02%, to hairless mouse skin immediately after exposure of the left flank to an erythemic dose of ultraviolet B light (UVB). This dose of UVB alone induces a sustained period of rapid epidermal cell proliferation, starting at about 18 h after the irradiation. Epidermal cell proliferation was followed from 18 to 54 h (0.005% cream) or from 18 to 30 h (0.02% cream) after the treatment by estimating the rate of G2-M cell flux (the mitotic rate) by means of Colcemid, and epidermal DNA synthesis by counting labeled cells after pulse-labeling with 3H-thymidine. The unirradiated side of the mice was used as reference. The results showed that topical treatment with a 0.02% EPP cream partially inhibited UVB-induced epidermal hyperproliferation, while the 0.005% EPP cream inhibited as well as stimulated the UVB-induced hyperproliferation. Thus, EPP is effective even in rapidly proliferating epidermal cell populations, but the outcome is obviously dose-dependent in this test system

Preconditioning With Low-Level Laser Irradiation Enhances the Therapeutic Potential of Human Adipose-derived Stem Cells in a Mouse Model of Photoaged Skin.

Science.gov (United States)

Liao, Xuan; Li, Sheng-Hong; Xie, Guang-Hui; Xie, Shan; Xiao, Li-Ling; Song, Jian-Xing; Liu, Hong-Wei

2018-02-19

This study was conducted to explore the therapeutic potential of human adipose-derived stem cells (ADSCs) irradiated with a low-level laser (LLL). Cultured ADSCs were treated with 650-nm GaAlAs laser irradiation at 2, 4 and 8 J cm -2 . Cell proliferation was quantified by MTT assays, cytokine secretion was determined by enzyme-linked immunosorbent assays, and adipogenic differentiation was examined by oil red O staining. Additionally, the expression profiles of putative ADSC surface markers were analyzed by quantitative real-time PCR. In addition, a mouse photoaged skin model was established by UVB irradiation. Effects of GaAlAs laser-treated ADSCs on the thicknesses of the epidermis and dermis were analyzed by hematoxylin and eosin staining. The results showed that GaAlAs laser treatment of cells at a radiant exposure of 4 J cm -2 enhanced ADSC proliferation and adipogenic differentiation and increased secretion of growth factors. Furthermore, GaAlAs laser irradiation upregulated the expression of putative ADSC surface markers. In the mouse model of photoaged skin, ADSCs treated with GaAlAs laser irradiation had markedly decreased the epidermal thickness and increased the dermal thickness of photoaged mouse skin. Our data indicate that LLL irradiation is an effective biostimulator of ADSCs and might enhance the therapeutic potential of ADSCs for clinical use. © 2018 The American Society of Photobiology.

Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice

DEFF Research Database (Denmark)

Erlendsson, Andrés M; Thaysen-Petersen, Daniel; Bay, Christiane

2016-01-01

BACKGROUND AND AIM: The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application...

Photocarcinogenesis and toxicity of benzoyl peroxide in hairless mice after simulated solar radiation

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas

2010-01-01

hairless female C3.Cg/TifBomTac-immunocompetent mice. BPO or BPO-clin was applied topically to the back five times each week, followed by SSR three times each week (2, 3, or 4 standard erythema doses) 3-4 h later, for 365 days or until death. Generally BPO and BPO-clin did not accelerate the time to first...

Photocarcinogenesis of topical tazarotene and isotretinoin alone and in combination with valproic acid in hairless mice

DEFF Research Database (Denmark)

Lerche, Catharina Margrethe; Philipsen, Peter Alshede; Sehested, Maxwell

2008-01-01

Retinoids and the histone deacetylase inhibitor valproic acid have shown anticancer properties, but the photocarcinogenic or photoprotective effect is unclear. Therefore, we investigated whether a topical formulation of valproic acid is photocarcinogenic or photoprotective in hairless female C3.Cg/Tif...

Quantitative Methods for Measuring Repair Rates and Innate-Immune Cell Responses in Wounded Mouse Skin

Directory of Open Access Journals (Sweden)

Zhi Li

2018-02-01

Full Text Available In skin wounds, innate-immune cells clear up tissue debris and microbial contamination, and also secrete cytokines and other growth factors that impact repair process such as re-epithelialization and wound closure. After injury, there is a rapid influx and efflux of immune cells at wound sites, yet the function of each innate cell population in skin repair is still under investigation. Flow cytometry is a valuable research tool for detecting and quantifying immune cells; however, in mouse back skin, the difficulty in extracting immune cells from small area of skin due to tissue complexity has made cytometric analysis an underutilized tool. In this paper, we provide detailed methods on the digestion of lesion-specific skin without disrupting antigen expression followed by multiplex cell staining that allows for identification of seven innate-immune populations, including rare subsets such as group-3 innate lymphoid cells (ILC3s, by flow-cytometry analysis. Furthermore, when studying the functions of immune cells to tissue repair an important metric to monitor is size of the wound opening. Normal wounds close steadily albeit at non-linear rates, while slow or stalled wound closure can indicate an underlying problem with the repair process. Calliper measurements are difficult and time-consuming to obtain and can require repeated sedation of experimental animals. We provide advanced methods for measuring of wound openness; digital 3D image capture and semi-automated image processing that allows for unbiased, reliable measurements that can be taken repeatedly over time.

Temporal aspects of tumorigenic response to individual and mixed carcinogens. Comprehensive progress report, June 1, 1975--May 31, 1978. [Mouse skin, rats, hamsters

Energy Technology Data Exchange (ETDEWEB)

Albert, R.E.; Burns, F.J.; Altshuler, B.

1978-02-01

The research proposed here is designed to obtain a better understanding of the temporal kinetics of tumor induction when one or more carcinogens are present simultaneously or sequentially for prolonged periods of time. Studies done to date under this contract have shown that carcinogenesis in mouse skin by polycyclic aromatic hydrocarbon carcinogens is consistent with the induction of dependent and autonomous cell transformations by the carcinogen followed by the conversion of autonomous tumor cells into malignancies at a rate which is determined by the level of carcinogen exposure. Dependent cell transformations remain latent in the skin unless expressed by a promoting agent. Dependent neoplasia appears to follow one-hit kinetics while malignancy is a multihit endpoint. Dose-related and time-related aspects of tumor induction are separable in the initiation-promotion system of mouse skin which along with rat skin and hamster lung is being used as a model for testing hypotheses. Results to date provide the basis for a new interpretation of the linear non-threshold extrapolation model. The broad aim of the study is to provide a basis or rationale for estimating risks associated with prolonged exposures to carcinogens found in the environment and to predict how different tissues and species respond to the same carcinogens.

A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

Science.gov (United States)

Jeon, Hyerin; Kim, Dong Hye; Nho, Youn-Hwa; Park, Ji-Eun; Kim, Su-Nam; Choi, Eung Ho

2016-01-01

Activation of peroxisome proliferator-activated receptors (PPAR) α/γ is known to inhibit the increases in matrix metalloproteinase (MMP) and reactive oxygen species (ROS) induced by ultraviolet light (UV). Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR) was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v) were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13) and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines) were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF)-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL) or stratum corneum (SC) integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL)-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation. PMID:27854351

A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

Directory of Open Access Journals (Sweden)

Hyerin Jeon

2016-11-01

Full Text Available Activation of peroxisome proliferator-activated receptors (PPAR α/γ is known to inhibit the increases in matrix metalloproteinase (MMP and reactive oxygen species (ROS induced by ultraviolet light (UV. Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13 and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL or stratum corneum (SC integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation.

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

International Nuclear Information System (INIS)

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-κB), we also investigated the effect of bromelain on Cox-2 and NF-κB expression. Results showed that bromelain application significantly inhibited Cox-2 and inactivated NF-κB by blocking phosphorylation and subsequent degradation of IκBα. 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-κB-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

Effect of Thai banana (Musa AA group) in reducing accumulation of oxidation end products in UVB-irradiated mouse skin.

Science.gov (United States)

Leerach, Nontaphat; Yakaew, Swanya; Phimnuan, Preeyawass; Soimee, Wichuda; Nakyai, Wongnapa; Luangbudnark, Witoo; Viyoch, Jarupa

2017-03-01

Chronic UVB exposure causes skin disorders and cancer through DNA strand breaks and oxidation of numerous functional groups of proteins and lipids in the skin. In this study, we investigated the effects of Thai banana (Musa AA group, "Khai," and Musa ABB group, "Namwa") on the prevention of UVB-induced skin damage when fed to male ICR mice. Mice were orally fed banana (Khai or Namwa) fruit pulps at dose of 1mg/g body weight/day for 12weeks. The shaved backs of the mice were irradiated with UVB for 12weeks. The intensity dose of UVB-exposure was increased from 54mJ/cm 2 /exposure at week 1 to 126mJ/cm 2 /exposure at week 12. A significant increase in skin thickness, lipid peroxidation, protein oxidation end products, and expression of MMP-1 was observed in UVB-irradiated mouse skin. A reduction in the accumulation of oxidation end products was found in the skin of UVB-irradiated mice receiving Khai. This occurred in conjunction with a reduction in MMP-1 expression, inhibition of epidermal thickening, and induction of γ-GCS expression. The dietary intake of Khai prevented skin damage from chronic UVB exposure by increased γ-GCS expression and reduced oxidation end products included carbonyls, malondialdehyde and 4-hydroxynonenal. Copyright © 2017 Elsevier B.V. All rights reserved.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

Science.gov (United States)

See, Gerard Lee; Sagesaka, Ayano; Sugasawa, Satoko; Todo, Hiroaki; Sugibayashi, Kenji

2017-11-25

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Tight Skin 2 Mice Exhibit Delayed Wound Healing Caused by Increased Elastic Fibers in Fibrotic Skin.

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Long, Kristen B; Burgwin, Chelsea M; Huneke, Richard; Artlett, Carol M; Blankenhorn, Elizabeth P

2014-09-01

Rationale: The Tight Skin 2 (Tsk2) mouse model of systemic sclerosis (SSc) has many features of human disease, including tight skin, excessive collagen deposition, alterations in the extracellular matrix (ECM), increased elastic fibers, and occurrence of antinuclear antibodies with age. A tight skin phenotype is observed by 2 weeks of age, but measurable skin fibrosis is only apparent at 10 weeks. We completed a series of wound healing experiments to determine how fibrosis affects wound healing in Tsk2/+ mice compared with their wild-type (WT) littermates. Method: We performed these experiments by introducing four 4 mm biopsy punched wounds on the back of each mouse, ventral of the midline, and observed wound healing over 10 days. Tsk2/+ mice showed significantly delayed wound healing and increased wound size compared with the WT littermates at both 5 and 10 weeks of age. We explored the potential sources of this response by wounding Tsk2/+ mice that were genetically deficient either for the NLRP3 inflammasome (a known fibrosis mediator), or for elastic fibers in the skin, using a fibulin-5 knockout. Conclusion: We found that the loss of elastic fibers restores normal wound healing in the Tsk2/+ mouse and that the loss of the NLRP3 inflammasome had no effect. We conclude that elastic fiber dysregulation is the primary cause of delayed wound healing in the Tsk2/+ mouse and therapies that promote collagen deposition in the tissue matrix in the absence of elastin deposition might be beneficial in promoting wound healing in SSc and other diseases.

Analysis of skin permeation-enhancing mechanism of iontophoresis using hydrodynamic pore theory.

Science.gov (United States)

Manabe, E; Numajiri, S; Sugibayashi, K; Morimoto, Y

2000-05-15

The effects of constant DC iontophoresis (0-1.5 mA/0.966 cm(2)) on the permeation of three hydrophilic compounds, antipyrine (ANP, M.W. 188.23), sucrose (SR, M.W. 342.30) and 1-kestose (KT, M.W. 506.73), through excised hairless rat skin were evaluated using hydrodynamic pore theory. The electro-osmotic flow caused by iontophoresis was measured using deuterium oxide (D(2)O). The penetration-enhancing mechanism of iontophoresis was found to increase solvent flow through electro-osmosis and pore enlargement and/or new pore production in the skin barrier, together with enhancement of electrochemical potential difference across the skin. These effects were closely related to the strength of the current applied. The electro-osmotic flow of D(2)O (J(D(2)O)) greatly enhanced the skin permeation clearance of all hydrophilic penetrants (CL(drug)). Pore production was classified into reversible and irreversible processes, which resulted from lower (0-0.5 mA/0.966 cm(2)) and higher (0.5-1. 5 mA/0.966 cm(2)) currents, respectively. Thus, the enhancing effects of iontophoresis on skin permeation of nonionic hydrophilic compounds can be explained by increase in pore size and higher solvent flow.

Effects of Ginsenoside Rb1 on Skin Changes

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Yoshiyuki Kimura

2012-01-01

Full Text Available Ginseng roots (Panax ginseng CA Meyer have been used traditionally for the treatment, especially prevention, of various diseases in China, Korea, and Japan. Both experimental and clinical studies suggest ginseng roots to have pharmacological effects in patients with life-style-related diseases such as non-insulin-dependent diabetic mellitus, atherosclerosis, hyperlipidemia, and hypertension. The topical use of ginseng roots to treat skin complaints including atopic suppurative dermatitis, wounds, and inflammation is also described in ancient Chinese texts; however, there have been relatively few studies in this area. In the present paper, we describe introduce the biological and pharmacological effects of ginsenoside Rb1 isolated from Red ginseng roots on skin damage caused by burn-wounds using male Balb/c mice (in vivo and by ultraviolet B irradiation using male C57BL/6J and albino hairless (HR-1 mice (in vivo. Furthermore, to clarify the mechanisms behind these pharmacological actions, human primary keratinocytes and the human keratinocyte cell line HaCaT were used in experiments in vitro.

Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin.

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Katiyar, Santosh K

2002-12-01

It is well documented that ultraviolet (UV) light-induced immune suppression and oxidative stress play an important role in the induction of skin cancers. Earlier, we have shown that topical treatment of silymarin, a plant flavonoid from milk thistle (Silybum marianum L. Gaertn.), to mouse skin prevents photocarcinogenesis, but the preventive mechanism of photocarcinogenesis in vivo animal system by silymarin is not well defined and understood. To define the mechanism of prevention, we employed immunostaining, analytical assays and ELISA which revealed that topical treatment of silymarin (1 mg/cm2 skin area) to C3H/HeN mice inhibits UVB (90 mJ/cm2)-induced suppression of contact hypersensitivity (CHS) response to contact sensitizer dinitrofluorobenzene. Prevention of UVB-induced suppression of CHS by silymarin was found to be associated with the inhibition of infiltrating leukocytes, particularly CD11b+ cell type, and myeloperoxidase activity (50-71%). Silymarin treatment also resulted in significant reduction of UVB-induced immunosuppressive cytokine interleukin-10 producing cells and its production (58-72%, pskin cancer risk human population and ii) development of sunscreen containing silymarin as an antioxidant (chemopreventive agent) or silymarin can be supplemented in skin care products.

Skin care products can aggravate epidermal function: studies in a murine model suggest a pathogenic role in sensitive skin.

Science.gov (United States)

Li, Zhengxiao; Hu, Lizhi; Elias, Peter M; Man, Mao-Qiang

2018-02-01

Sensitive skin is defined as a spectrum of unpleasant sensations in response to a variety of stimuli. However, only some skin care products provoke cutaneous symptoms in individuals with sensitive skin. Hence, it would be useful to identify products that could provoke cutaneous symptoms in individuals with sensitive skin. To assess whether vehicles, as well as certain branded skin care products, can alter epidermal function following topical applications to normal mouse skin. Following topical applications of individual vehicle or skin care product to C57BL/6J mice twice daily for 4 days, transepidermal water loss (TEWL) rates, stratum corneum (SC) hydration and skin surface pH were measured on treated versus untreated mouse skin with an MPA5 device and pH 900 pH meter. Our results show that all tested products induced abnormalities in epidermal functions of varying severity, including elevations in TEWL and skin surface pH, and reduced SC hydration. Our results suggest that mice can serve as a predictive model that could be used to evaluate the potential safety of skin care products in humans with sensitive skin. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development of an in vivo animal model for skin penetration in hairless rats assessed by mass balance

DEFF Research Database (Denmark)

Simonsen, Lene; Petersen, Mads B; Benfeldt, Eva

2002-01-01

acid and (14)C-butyl salicylate were topically applied. Rapid and differentiated percutaneous absorption of both compounds were shown by urinary excretion data. For (14)C-salicylic acid the amount on the skin surface, in the stratum corneum and in the viable skin was determined. Total mass balance...... rat and free mobility throughout the test period. By consecutive tape stripping, monitored by measurements of transepidermal water loss and confirmed by histological examination of skin biopsies, 10 tape strippings were found to remove the stratum corneum completely. For assessment of the model, (14)C-salicylic...

Leptin promotes wound healing in the skin.

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Susumu Tadokoro

Full Text Available Leptin, a 16 kDa anti-obesity hormone, exhibits various physiological properties. Interestingly, skin wound healing was proven to delay in leptin-deficient ob/ob mice. However, little is known on the mechanisms of this phenomenon. In this study, we attempted to elucidate a role of leptin in wound healing of skin.Immunohistochemical analysis was performed to confirm the expression of the leptin receptor (Ob-R in human and mouse skin. Leptin was topically administered to chemical wounds created in mouse back skin along with sustained-release absorbable hydrogel. The process of wound repair was histologically observed and the area of ulceration was measured over time. The effect of leptin on the proliferation, differentiation and migration of human epidermal keratinocytes was investigated.Ob-R was expressed in epidermal cells of human and mouse skin. Topical administration of leptin significantly promoted wound healing. Histological analysis showed more blood vessels in the dermal connective tissues in the leptin-treated group. The proliferation, differentiation/function and migration of human epidermal keratinocytes were enhanced by exogenous leptin.Topically administered leptin was proven to promote wound healing in the skin by accelerating proliferation, differentiation/function and migration of epidermal keratinocytes and enhancing angiogenesis around the wounded area. These results strongly suggest that topical administration of leptin may be useful as a treatment to promote wound healing in the skin.

Analysis of the interaction between human RITA and Drosophila Suppressor of Hairless.

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Brockmann, Birgit; Mastel, Helena; Oswald, Franz; Maier, Dieter

2014-12-01

Notch signalling mediates intercellular communication, which is effected by the transcription factor CSL, an acronym for vertebrate CBF1/RBP-J, Drosophila Suppressor of Hairless [Su(H)] and C. elegans Lag1. Nuclear import of CBF1/RBP-J depends on co-activators and co-repressors, whereas the export relies on RITA. RITA is a tubulin and CBF1/RBP-J binding protein acting as a negative regulator of Notch signalling in vertebrates. RITA protein is highly conserved in eumatazoa, but no Drosophila homologue was yet identified. In this work, the activity of human RITA in the fly was addressed. To this end, we generated transgenic flies that allow a tissue specific induction of human RITA, which was demonstrated by Western blotting and in fly tissues. Unexpectedly, overexpression of RITA during fly development had little phenotypic consequences, even when overexpressed simultaneously with either Su(H) or the Notch antagonist Hairless. We demonstrate the in vivo binding of human RITA to Su(H) and to tubulin by co-immune precipitation. Moreover, RITA and tubulin co-localized to some degree in several Drosophila tissues. Overall our data show that human RITA, albeit binding to Drosophila Su(H) and tubulin, cannot influence the Notch signalling pathway in the fly, suggesting that a nuclear export mechanism of Su(H), if existent in Drosophila, does not depend on RITA. © 2015 The Authors.

The skin migratory stage of the schistosomulum of Schistosoma mansoni has a surface showing greater permeability and activity in membrane internalisation than other forms of skin or mechanical schistosomula.

Science.gov (United States)

DE Jesus Jeremias, Wander; DA Cunha Melo, Jose Renan; Baba, Elio Hideo; Coelho, Paulo Marcos Zech; Kusel, John Robert

2015-08-01

Skin schistosomula can be prepared by collecting them after isolated mouse skin have been penetrated by cercariae in vitro. The schistosomula can also migrate out of isolated mouse skin penetrated by cercariae in vitro and from mouse skin penetrated by cercariae in vivo. Schistosomula can also be produced from cercariae applied through a syringe or in a vortex. When certain surface properties of the different forms of schistosomula were compared, those migrating from mouse skin penetrated by cercariae in vivo or in vitro had greatly increased permeability to membrane impermeant molecules such as Lucifer yellow and high molecular weight dextrans. These migrating forms also possessed surfaces which showed greatly enhanced uptake into internal membrane vesicles of the dye FM 143, a marker for endocytosis. This greatly enhanced activity and permeability of the surfaces of tissue migrating schistosomula is likely to be of great importance in the adaptation to the new host.

Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin

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Montserrat Rojo de la Vega

2018-03-01

Full Text Available Environmental exposure to solar ultraviolet (UV radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana. Here, we tested the feasibility of topical use of bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-]. First, we observed that a bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical bixin suppresses PUVA (psoralen + UVA-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches.

Topical Bixin Confers NRF2-Dependent Protection Against Photodamage and Hair Graying in Mouse Skin

Science.gov (United States)

Rojo de la Vega, Montserrat; Zhang, Donna D.; Wondrak, Georg T.

2018-01-01

Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/-)]. First, we observed that a bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches. PMID:29636694

Investigation of skin cancer treatment efficiency by raman spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Lee, M. S.; Kim, D. W. [Kyungpook National University, Taegu (Korea)

2000-04-01

From the successful perform of the molecular structures of various kinds of human skin cancer. We can predict the types of cancer when a small abnormal change change occurs on skin by raman spectrum. When we applied the cancer causing chemicals, bezopyrene, to nude mouse, it did not develop to cancer. But we had radiated UV light after developed to skin cancer in a few days. We can deduce the development of human skin cancer from the result of nude mouse skin cancer, because the two skin are structurally very similar to each other. From the results of own research we could conform the UV light is essential for the development of skin cancer. The results of own research can be directly apply to early detection and proper treatment of skin cancer in hospital. 32 refs., 40 figs., 16 tabs. (Author)

Gender-related effects on substrate utilization and metabolic adaptation in hairless spontaneously hypertensive rat

Czech Academy of Sciences Publication Activity Database

Trnovská, J.; Šilhavý, Jan; Zídek, Václav; Šimáková, Miroslava; Mlejnek, Petr; Landa, Vladimír; Eigner, Sebastian; Eigner-Henke, Kateřina; Škop, V.; Oliyarnyk, O.; Kazdová, L.; Mráček, Tomáš; Houštěk, Josef; Pravenec, Michal

2015-01-01

Roč. 64, č. 1 (2015), s. 51-60 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GB14-36804G; GA ČR(CZ) GA13-04420S; GA MŠk(CZ) LL1204; GA MZd(CZ) NT14325 Institutional support: RVO:67985823 ; RVO:61389005 Keywords : gender * hairless rat * metabolism * brown adipose tissue Subject RIV: ED - Physiology Impact factor: 1.643, year: 2015

Stokes shift spectroscopy for the early diagnosis of epithelial precancers in DMBA treated mouse skin carcinogenesis

Science.gov (United States)

Jeyasingh, Ebenezar; Singaravelu, Ganesan; Prakasarao, Aruna

2018-02-01

In this study, we aim to characterize the tissue transformation in dimethylbenz(a)anthracene (DMBA) treated mouse skin tumor model using stokes shift spectroscopy (SSS) technique for early detection of the neoplastic changes. Stokes shift (SS) spectra measured by scanning both excitation and emission wavelength simultaneously with a fixed wavelength of interval (Δλ=20 nm) in vivo from 33 DMBA treated animals and 6 control animals. The SS spectra of normal (n=6), hyperplasia (n=10), dysplasia (n=10), and WDSCC (n=13) of mice skin shows the distinct peaks around 300, 350, and 386 nm may be attributed to tryptophan, collagen, and NADH respectively. From the observed spectral differences and the ratio variables that resulted in better classification between groups, it is concluded that tryptophan, collagen, and NADH are the key fluorophores that undergo changes during tissue transformation process and hence they can be targeted as tumor markers for early neoplastic changes.

Platelet-Rich Fibrin Accelerates Skin Wound Healing in Diabetic Mice.

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Ding, Yinjia; Cui, Lei; Zhao, Qiming; Zhang, Weiqiang; Sun, Huafeng; Zheng, Lijun

2017-09-01

Diabetic foot ulcers (DFUs) are associated with an increased risk of secondary infection and amputation. Platelet-rich fibrin (PRF), a platelet and leukocyte concentrate containing several cytokines and growth factors, is known to promote wound healing. However, the effect of PRF on diabetic wound healing has not been adequately investigated. The aim of the study was to investigate the effect of PRF on skin wound healing in a diabetic mouse model. Platelet-rich fibrin was prepared from whole blood of 8 healthy volunteers. Two symmetrical skin wounds per mouse were created on the back of 16 diabetic nude mice. One of the 2 wounds in each mouse was treated with routine dressings (control), whereas the other wound was treated with PRF in addition to routine dressings (test), each for a period of 14 days. Skin wound healing rate was calculated.Use of PRF was associated with significantly improved skin wound healing in diabetic mice. On hematoxylin and eosin and CD31 staining, a significant increase in the number of capillaries and CD31-positive cells was observed, suggesting that PRF may have promoted blood vessel formation in the skin wound. In this study, PRF seemed to accelerate skin wound healing in diabetic mouse models, probably via increased blood vessel formation.

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

International Nuclear Information System (INIS)

Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

2011-01-01

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-FT TM ). 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.

Comparative Effects of Retinoic Acid or Glycolic Acid Vehiculated in Different Topical Formulations

Science.gov (United States)

Maia Campos, Patrícia Maria Berardo Gonçalves; Gaspar, Lorena Rigo; Gonçalves, Gisele Mara Silva; Pereira, Lúcia Helena Terenciane Rodrigues; Semprini, Marisa; Lopes, Ruberval Armando

2015-01-01

Retinoids and hydroxy acids have been widely used due to their effects in the regulation of growth and in the differentiation of epithelial cells. However, besides their similar indication, they have different mechanisms of action and thus they may have different effects on the skin; in addition, since the topical formulation efficiency depends on vehicle characteristics, the ingredients of the formulation could alter their effects. Thus the objective of this study was to compare the effects of retinoic acid (RA) and glycolic acid (GA) treatment on the hairless mouse epidermis thickness and horny layer renewal when added in gel, gel cream, or cream formulations. For this, gel, gel cream, and cream formulations (with or without 6% GA or 0.05% RA) were applied in the dorsum of hairless mice, once a day for seven days. After that, the skin was analyzed by histopathologic, morphometric, and stereologic techniques. It was observed that the effects of RA occurred independently from the vehicle, while GA had better results when added in the gel cream and cream. Retinoic acid was more effective when compared to glycolic acid, mainly in the cell renewal and the exfoliation process because it decreased the horny layer thickness. PMID:25632398

Commonly Employed African Neonatal Skin Care Products Compromise Epidermal Function in Mice.

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Man, Mao-Qiang; Sun, Richard; Man, George; Lee, Dale; Hill, Zelee; Elias, Peter M

2016-09-01

Neonatal mortality is much higher in the developing world than in developed countries. Infections are a major cause of neonatal death, particularly in preterm infants, in whom defective epidermal permeability barrier function facilitates transcutaneous pathogen invasion. The objective was to determine whether neonatal skin care products commonly used in Africa benefit or compromise epidermal functions in murine skin. After twice-daily treatment of 6- to 8-week-old hairless mice with each skin care product for 3 days, epidermal permeability barrier function, skin surface pH, stratum corneum hydration, and barrier recovery were measured using a multiprobe adapter system physiology monitor. For products showing some benefits in these initial tests, the epidermal permeability barrier homeostasis was assessed 1 and 5 hours after a single application to acutely disrupted skin. All of the skin care products compromised basal permeability barrier function and barrier repair kinetics. Moreover, after 3 days of treatment, most of the products also reduced stratum corneum hydration while elevating skin surface pH to abnormal levels. Some neonatal skin care products that are widely used in Africa perturb important epidermal functions, including permeability barrier homeostasis in mice. Should these products have similar effects on newborn human skin, they could cause a defective epidermal permeability barrier, which can increase body fluid loss, impair thermoregulation, and contribute to the high rates of neonatal morbidity and mortality seen in Africa. Accordingly, alternative products that enhance permeability barrier function should be identified, particularly for use in preterm infants. © 2016 Wiley Periodicals, Inc.

Human reconstructed skin xenografts on mice to model skin physiology.

Science.gov (United States)

Salgado, Giorgiana; Ng, Yi Zhen; Koh, Li Fang; Goh, Christabelle S M; Common, John E

Xenograft models to study skin physiology have been popular for scientific use since the 1970s, with various developments and improvements to the techniques over the decades. Xenograft models are particularly useful and sought after due to the lack of clinically relevant animal models in predicting drug effectiveness in humans. Such predictions could in turn boost the process of drug discovery, since novel drug compounds have an estimated 8% chance of FDA approval despite years of rigorous preclinical testing and evaluation, albeit mostly in non-human models. In the case of skin research, the mouse persists as the most popular animal model of choice, despite its well-known anatomical differences with human skin. Differences in skin biology are especially evident when trying to dissect more complex skin conditions, such as psoriasis and eczema, where interactions between the immune system, epidermis and the environment likely occur. While the use of animal models are still considered the gold standard for systemic toxicity studies under controlled environments, there are now alternative models that have been approved for certain applications. To overcome the biological limitations of the mouse model, research efforts have also focused on "humanizing" the mice model to better recapitulate human skin physiology. In this review, we outline the different approaches undertaken thus far to study skin biology using human tissue xenografts in mice and the technical challenges involved. We also describe more recent developments to generate humanized multi-tissue compartment mice that carry both a functioning human immune system and skin xenografts. Such composite animal models provide promising opportunities to study drugs, disease and differentiation with greater clinical relevance. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Modulation of accelerated repopulation in mouse skin during daily irradiation

International Nuclear Information System (INIS)

Trott, K.-R.; Shirazi, A.; Heasman, F.

1999-01-01

Background and purpose: The timing of acceleration of repopulation in the epidermis during daily irradiation is related to the development of skin erythema and epidermal hypoplasia. Therefore, the relationship between impairment of the epidermal barrier function, the dermal inflammatory response and epidermal hypoplasia with the acceleration of repopulation was investigated.Materials and purpose: Skin fields of approximately 1 cm 2 on the thighs of TUC mice were given five daily fractions of 3 Gy in each week followed by top-up doses at the end of the first, the second, or the third week to determine residual epidermal tolerance and to calculate repopulation rates in weeks 1, 2, or 3. Systemic modulation of repopulation was attempted by daily indomethacine during fractionated irradiation whereas tape stripping or UV-B exposure before the start of fractionated irradiation attempted local modulation. In parallel experiments, the water permeability coefficient of the epidermis was determined ex vivo by studying transepidermal transport of tritiated water.Results: Without modulation, no repopulation was found in the first week of daily fractionation but repopulation compensated 30% of the dose given in week two and 70% of the dose given in week three. Only tape stripping before the start of fractionated irradiation accelerated repopulation in week one. UV-B had no effect on repopulation although it stimulated proliferation as much as tape stripping. Indomethacin did not suppress acceleration of repopulation. A significant increase in transepidermal water loss was found but only after repopulation had already accelerated.Conclusions: Acceleration of repopulation in mouse epidermis during daily-fractionated irradiation is not related to the simultaneous development of an inflammatory response. Also, the loss of the epidermal barrier function is not involved in the development of the acceleration response, which rather seems to be triggered directly by the decreased

Skin care products can aggravate epidermal function: studies in a murine model suggest a pathogenic role in sensitive skin

OpenAIRE

Li, Z; Hu, L; Elias, PM; Man, M-Q

2018-01-01

Sensitive skin is defined as a spectrum of unpleasant sensations in response to a variety of stimuli. However, only some skin care products provoke cutaneous symptoms in individuals with sensitive skin. Hence, it would be useful to identify products that could provoke cutaneous symptoms in individuals with sensitive skin.To assess whether vehicles, as well as certain branded skin care products, can alter epidermal function following topical applications to normal mouse skin.Following topical ...

Sunscreens for delay of ultraviolet induction of skin tumors

International Nuclear Information System (INIS)

Wulf, H.C.; Poulsen, T.; Brodthagen, H.; Hou-Jensen, K.

1982-01-01

Sunscreens with different sun protection factors (SPFs) have been tested for their capability of delaying or preventing actinic damage and skin cancer development in groups of hairless, pigmented mice exposed to artificial ultraviolet (UV) light of increasing intensity. The dose delivered was less than or equal to 1 minimal erythema dose (MED) in the group of untreated mice, so that the mice to which sunscreens were applied never obtained a sunburn after UV exposure. The quality of UV light was similar to bright midday sun at a latitude of 56 degrees (city of Copenhagen). Tumorigenesis was demonstrated to be delayed corresponding to the SPF claimed by the manufacturer, but almost all of the UV-irradiated mice developed skin tumors. Histologic examination revealed actinic degeneration and tumors of squamous cell type with marked variation in differentiation. Metastases to lymph nodes and lungs were found in only 10%. Toxic reactions, such as eczematous-like skin reactions, dark coloring, and amyloidosis, were observed predominantly in the group treated with the sunscreen of highest SPF value. Long-term investigations seem to be necessary to unveil these problems--in particular, the specific SPF value, in sunscreens, that should be recommended to the public for prevention or delay of actinic damage and/or cancer development

Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction.

Science.gov (United States)

Shin, Mi Hee; Lee, Se-Rah; Kim, Min-Kyoung; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2016-01-01

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging.

Dosimetry of skin-contact exposure to tritium gas contaminated surfaces

International Nuclear Information System (INIS)

Legare, M.

1990-12-01

The radiological hazards from tritium are usually associated with exposure to tritium oxide either by inhalation, ingestion or permeation through skin. However, exposure from skin contact with tritium gas contaminated surfaces represents a different radiological hazard in tritium removal facilities and future fusion power plants. Previous experiments on humans and more recent experiments on hairless rats at Chalk River Laboratories have shown that when a tritium gas-contaminated surface is brought into contact with intact skin, high concentrations of organically-bound tritium in urine and skin are observed which were not seen from single tritiated water (liquid or vapour form) contamination. The results of the rat experiments, which involved measurements of tritium activity in urine and skin, after contact with contaminated stainless steel, are described. These results are also compared to previous data from human experiments. The effect of various exposure conditions and different contaminated surfaces such as brass, aluminum and glass are analysed and related to the results from contaminated stainless steel exposure. Dosimetric models are being developed in order to improve the basis for dose assessment for this mode of tritium uptake. The presently studied model is explained along with the assumptions and methods involved in its derivation. The features of 'STELLA', the software program used to implement the model, are discussed. The methods used to estimate skin and whole body dose from a model are demonstrated. Finally, some experiments for improving the accuracy of the model are proposed. Briefly, this study compares the results from animal and human experiments as well as different exposure conditions, and determines the range of whole body and skin dose that may be involved from skin-contact intake. This information is essential for regulatory purposes particularly in the derivation of doses for skin-contact contamination. (15 figs., 7 tabs., 29 refs.)

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.

Science.gov (United States)

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. © 2014 Japanese Dermatological Association.

Peroxisome proliferator-activated receptor δ modulates MMP-2 secretion and elastin expression in human dermal fibroblasts exposed to ultraviolet B radiation.

Science.gov (United States)

Ham, Sun Ah; Yoo, Taesik; Hwang, Jung Seok; Kang, Eun Sil; Paek, Kyung Shin; Park, Chankyu; Kim, Jin-Hoi; Do, Jeong Tae; Seo, Han Geuk

2014-10-01

Changes in skin connective tissues mediated by ultraviolet (UV) radiation have been suggested to cause the skin wrinkling normally associated with premature aging of the skin. Recent investigations have shown that peroxisome proliferator-activated receptor (PPAR) δ plays multiple biological roles in skin homeostasis. We attempted to investigate whether PPARδ modulates elastin protein levels and secretion of matrix metalloproteinase (MMP)-2 in UVB-irradiated human dermal fibroblasts (HDFs) and mouse skin. These studies were undertaken in primary HDFs or HR-1 hairless mice using Western blot analyses, small interfering (si)RNA-mediated gene silencing, and Fluorescence microscopy. In HDFs, UVB irradiation induced increased secretion of MMP-2 and reduced levels of elastin. Activation of PPARδ by GW501516, a ligand specific for PPARδ, markedly attenuated UVB-induced MMP-2 secretion with a concomitant increase in the level of elastin. These effects were reduced by the presence of siRNAs against PPARδ or treatment with GSK0660, a specific inhibitor of PPARδ. Furthermore, GW501516 elicited a dose- and time-dependent increase in the expression of elastin. Modulation of MMP-2 secretion and elastin levels by GW501516 was associated with a reduction in reactive oxygen species (ROS) production in HDFs exposed to UVB. Finally, in HR-1 hairless mice, administration of GW501516 significantly reduced UVB-induced MMP-2 expression with a concomitant increase in elastin levels, and these effects were significantly reduced by the presence of GSK0660. Our results suggest that PPARδ-mediated modulation of MMP-2 secretion and elastin expression may contribute to the maintenance of skin integrity by inhibiting ROS generation. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

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

International Nuclear Information System (INIS)

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

2009-01-01

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

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

Directory of Open Access Journals (Sweden)

Wu Minjuan

2016-01-01

Full Text Available 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.

Validity of reciprocity rule on mouse skin thermal damage due to CO2 laser irradiation

Science.gov (United States)

Parvin, P.; Dehghanpour, H. R.; Moghadam, M. S.; Daneshafrooz, V.

2013-07-01

CO2 laser (10.6 μm) is a well-known infrared coherent light source as a tool in surgery. At this wavelength there is a high absorbance coefficient (860 cm-1), because of vibration mode resonance of H2O molecules. Therefore, the majority of the irradiation energy is absorbed in the tissue and the temperature of the tissue rises as a function of power density and laser exposure duration. In this work, the tissue damage caused by CO2 laser (1-10 W, ˜40-400 W cm-2, 0.1-6 s) was measured using 30 mouse skin samples. Skin damage assessment was based on measurements of the depth of cut, mean diameter of the crater and the carbonized layer. The results show that tissue damage as assessed above parameters increased with laser fluence and saturated at 1000 J cm-2. Moreover, the damage effect due to high power density at short duration was not equivalent to that with low power density at longer irradiation time even though the energy delivered was identical. These results indicate the lack of validity of reciprocity (Bunsen-Roscoe) rule for the thermal damage.

A dicyanotriterpenoid induces cytoprotective enzymes and reduces multiplicity of skin tumors in UV-irradiated mice

International Nuclear Information System (INIS)

Dinkova-Kostova, Albena T.; Jenkins, Stephanie N.; Wehage, Scott L.; Huso, David L.; Benedict, Andrea L.; Stephenson, Katherine K.; Fahey, Jed W.; Liu Hua; Liby, Karen T.; Honda, Tadashi; Gribble, Gordon W.; Sporn, Michael B.; Talalay, Paul

2008-01-01

Inducible phase 2 enzymes constitute a primary line of cellular defense. The oleanane dicyanotriterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (TP-225) is a very potent inducer of these systems. Topical application of TP-225 to SKH-1 hairless mice increases the levels of NAD(P)H-quinone acceptor oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1) and protects against UV radiation-induced dermal thickening. Daily topical treatments of 10 nmol of TP-225 to the backs of mice that were previously subjected to low-level chronic UVB radiation (30 mJ/cm 2 /session, twice a week for 17 weeks), led to 50% reduction in multiplicity of skin tumors. In addition, the total tumor burden of squamous cell carcinomas was reduced by 5.5-fold. The identification of new agents for protection against UV radiation-induced skin cancer and understanding of their mechanism(s) of action is especially important in view of the fact that human skin cancers represent a significant source of increasing morbidity and mortality

The effect of bamboo (Phyllostachys nigra var. henenis Strapf) leaf extract on ultraviolet B-induced skin damages in mouse

International Nuclear Information System (INIS)

Chae, Se Lim; Lee, Hae June; Moon, Chang Jong; Kim, Jong Choon; Bae, Chun Sik; Kang, Seong Soo; Kim, Sung Ho; Jang, Jong Sik; Jo, Sung Kee

2007-01-01

The effects of bamboo (Phyllostachys nigra var. henenis Strapf) Leaf Extract (BLE) on the changes of UltraViolet (UV) light B radiation-induced apoptotic SunBurn Cell (SBC) and epidermal ATPase-positive Dendritic Cell (DC) in SKHI-hr or ICR mouse were investigated. The mice were treated with UVB (200 mJ/cm 2 ) and were sacrificed 24 hours later. BLE (50 mg/kg of body weight) or vehicle (saline) was given i.p. at 36 and 12 hours before irradiation, and 30 minutes after irradiation. BLE cream (0.2%) or cream base (vehicle) was also topically treated at 24 hours and 15 minutes before irradiation, and immediately after irradiation. The skin of SKH1-hr mouse prepared from the back of untreated mice exhibited about 0.3 SBC/cm length of epidermis, and 24 hours after UV irradiation, the applied areas show an increased number of SBCs. But the frequency of UVB-induced SBC formation was significantly reduced by intraperitoneal injection (59.0%) and topical application (31.8%) of BLE extract. The numbers of DC in normal ICR mouse were 628.00±51.56 or 663.20±62.58 per mm 2 of ear epidermis. By 1 day after UVB treatment, the number of ATPase-positive cells/mm 2 were decreased by 39.0% or 27.1% in i.p. or topical application group with vehicle. The frequency of UVB(200 mJ/cm 2 )-induced DC decrease was reduced by treatment of BLE as 25.7% in i.p. group and 3.2% in topical application group compared with the irradiation control group. The results presented herein that BLE administration could reduce the extent of skin damages produced by UVB

The effect of bamboo (Phyllostachys nigra var. henenis Strapf) leaf extract on ultraviolet B-induced skin damages in mouse

Energy Technology Data Exchange (ETDEWEB)

Chae, Se Lim; Lee, Hae June; Moon, Chang Jong; Kim, Jong Choon; Bae, Chun Sik; Kang, Seong Soo; Kim, Sung Ho [Chonnam National Univ., Gwangju (Korea, Republic of); Jang, Jong Sik [Sangju National Univ., Sangju (Korea, Republic of); Jo, Sung Kee [KAERI, Daejeon (Korea, Republic of)

2007-06-15

The effects of bamboo (Phyllostachys nigra var. henenis Strapf) Leaf Extract (BLE) on the changes of UltraViolet (UV) light B radiation-induced apoptotic SunBurn Cell (SBC) and epidermal ATPase-positive Dendritic Cell (DC) in SKHI-hr or ICR mouse were investigated. The mice were treated with UVB (200 mJ/cm{sup 2}) and were sacrificed 24 hours later. BLE (50 mg/kg of body weight) or vehicle (saline) was given i.p. at 36 and 12 hours before irradiation, and 30 minutes after irradiation. BLE cream (0.2%) or cream base (vehicle) was also topically treated at 24 hours and 15 minutes before irradiation, and immediately after irradiation. The skin of SKH1-hr mouse prepared from the back of untreated mice exhibited about 0.3 SBC/cm length of epidermis, and 24 hours after UV irradiation, the applied areas show an increased number of SBCs. But the frequency of UVB-induced SBC formation was significantly reduced by intraperitoneal injection (59.0%) and topical application (31.8%) of BLE extract. The numbers of DC in normal ICR mouse were 628.00{+-}51.56 or 663.20{+-}62.58 per mm{sup 2} of ear epidermis. By 1 day after UVB treatment, the number of ATPase-positive cells/mm{sup 2} were decreased by 39.0% or 27.1% in i.p. or topical application group with vehicle. The frequency of UVB(200 mJ/cm{sup 2})-induced DC decrease was reduced by treatment of BLE as 25.7% in i.p. group and 3.2% in topical application group compared with the irradiation control group. The results presented herein that BLE administration could reduce the extent of skin damages produced by UVB.

Development of a codrug approach for sustained drug delivery across microneedle-treated skin.

Science.gov (United States)

Ghosh, Priyanka; Pinninti, Raghotham R; Hammell, Dana C; Paudel, Kalpana S; Stinchcomb, Audra L

2013-05-01

Microneedle (MN) enhanced transdermal drug delivery enables the transport of a host of molecules that cannot be delivered across the skin by passive diffusion alone. However, the skin being a self-regenerating organ heals itself and thus prevents delivery of molecules through micropores for a 7-day time period, the ideal transdermal delivery goal. Hence, it is necessary to employ a second drug molecule, a cyclooxygenase inhibitor to enhance pore lifetime by decreasing local subclinical inflammatory response following MN treatment. A codrug approach using a 3-O-ester codrug of the model drug naltrexone (NTX) with diclofenac (DIC), a cyclooxygenase inhibitor, was tested in vitro as well as in vivo to look at stability, bioconversion and permeation. The results indicated that the approach could be useful for transdermal drug delivery of NTX from a single patch for a week, but stability and solubility optimization will be required for the codrug before it can deliver significant levels of NTX into the plasma. The skin concentration of DIC was high enough to keep the pores open in vivo in a hairless guinea pig model as demonstrated by day seven pore visualization studies. Copyright © 2013 Wiley Periodicals, Inc.

UV decreases the synthesis of free fatty acids and triglycerides in the epidermis of human skin in vivo, contributing to development of skin photoaging.

Science.gov (United States)

Kim, Eun Ju; Jin, Xing-Ji; Kim, Yeon Kyung; Oh, In Kyung; Kim, Ji Eun; Park, Chi-Hyun; Chung, Jin Ho

2010-01-01

Although fatty acids are known to be important in various skin functions, their roles on photoaging in human skin are poorly understood. We investigated the alteration of lipid metabolism in the epidermis by photoaging and acute UV irradiation in human skin. UV irradiated young volunteers (21-33 years, n=6) and elderly volunteers (70-75 years, n=7) skin samples were obtained by punch biopsy. Then the epidermis was separated from dermis and lipid metabolism was investigated. We observed that the amounts of free fatty acids (FFA) and triglycerides (TG) in the epidermis of photoaged or acutely UV irradiated human skin were significantly decreased. The expressions of genes related to lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPARgamma) were also markedly decreased. To elucidate the significance of these changes of epidermal lipids in human skin, we investigated the effects of TG or various inhibitors for the enzymes involved in TG synthesis on the expression of matrix metalloproteinase-1 (MMP-1) in cultured human epidermal keratinocytes. We demonstrated that triolein (TG) reduced basal and UV-induced MMP-1 mRNA expression. In addition, each inhibitor for various lipid synthesis enzymes, such as TOFA (ACC inhibitor), cerulenin (FAS inhibitor) and trans-10, cis-12-CLA (SCD inhibitor), increased the MMP-1 expression significantly in a dose-dependent manner. We also demonstrated that triolein could inhibit cerulenin-induced MMP-1 expression. Furthermore, topical application of triolein (10%) significantly prevented UV-induced MMP-13, COX-2, and IL-1beta expression in hairless mice. Our results suggest that TG and FFA may play important roles in photoaging of human skin. Copyright 2009 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

ATR-FTIR and Raman spectroscopic investigation of the electroporation-mediated transdermal delivery of a nanocarrier system containing an antitumour drug.

Science.gov (United States)

Balázs, Boglárka; Sipos, Péter; Danciu, Corina; Avram, Stefana; Soica, Codruta; Dehelean, Cristina; Varju, Gábor; Erős, Gábor; Budai-Szűcs, Mária; Berkó, Szilvia; Csányi, Erzsébet

2016-01-01

The aim of the present work was the optimization of the transdermal delivery of a lyotropic liquid crystal genistein-based formulation (LLC-GEN). LLC was chosen as medium in view of the poor solubility of GEN in water. Membrane diffusion and penetration studies were carried out with a Franz diffusion cell, through a synthetic membrane in vitro, a chick chorioallantoic membrane ex ovo, and ex vivo excised human epidermis. Thereafter, LLC-GEN was combined with electroporation (EP) to enhance the transdermal drug delivery. The synergistic effect of EP was verified by in vivo ATR-FTIR and ex vivo Raman spectroscopy on hairless mouse skin.

The response of mouse skin to multiple small doses of radiation

International Nuclear Information System (INIS)

Denekamp, J.; Harris, S.R.

1975-01-01

The response of mouse skin has been tested by irradiating the foot of albino mice and scoring erythema and desquamation during the following month. Multiple small doses of 150, 250 and 350 rad have been given 'daily', and the test dose necessary to achieve a given reaction has been determined one day after the last small fraction. This test dose has been compared with the single dose necessary to produce the same reaction level in previously untreated mice, in order to determine the ratio of the slopes of the dose-response curve at low and high doses: Slope ratio = (single dose - test dose)/total fractionated priming dose. In three separate experiments the slope ratio decreased as the dose per fraction was reduced from 350 to 150 rad. This conflicts with the data of Dutreix et al, who found a constant slope ratio over this dose range. The present data are compared with those obtained by Denekamp using 4, 9 and 14 fractions of 300 rad and by Douglas et al, using the same experimental technique, over the dose range 45 to 200 rad/fraction. In addition, the results from multifraction experiments in which equal dose increments were administered until the requisite skin reaction was achieved are also analysed in terms of their slope ratio (Fowler et al. Douglas et al). When all these results are plotted it is impossible to be sure whether the slope ratio is decreasing over the range 300 to 45 rad per fraction, although it seems likely. Most of the values at low doses lie in the range 0.15 to 0.25, indicating that at low doses the radiation is only 15 to 25% as effective per rad in causing cell death as at higher doses. (author)

Inhalation and Percutaneous Toxicokinetics of Sulfur Mustard and Its adducts in Hairless Guinea Pigs and Marmosets. Efficacy of Nasal Scavengers

National Research Council Canada - National Science Library

Langenberg, Jan P

2004-01-01

As a follow-up to DAMDl7-94-V-4OO9, the inhalation toxicokinetics of sulfur mustard are studied in more detail in the hairless guinea pig as well as in a species more relevant for man, i.e., the marmoset...

Reduction of radiation-induced early skin damage (mouse foot) by 0-(β-hydroxyaethyl)-rutoside

International Nuclear Information System (INIS)

Fritz-Niggli, H.; Froehlich, E.

1980-01-01

The effect of a bioflavonoid, 0-(β-hydroxyethyl)-rutoside (HR) on early radiation-induced skin damage was examined, using the mouse foot system; the response to radiation is not species specific and comparison with the clinical situation is therefore possible. The aim was to see whether HR, which is highly effective in protecting against late damage, is also able to reduce early effects. Early reactions were considered to be erythema, swelling and ulceration and occurring up to 30 days after irradiation. It was found that HR significantly reduces early damage, both after a single dose and after fractionated irradiation with low doses. A single pre-treatment dose of HR and pre-treatment together with 30 days post-treatment administration were both found to be effective. The protective effect became more marked with increasing radiation dose (single irradiation). Reduction of late effects is produced iptimally by an interval of 0.25 hours between application of HR and irradiation, and this is also true for early skin damage. The early effects are partly reversible, but there is possibly an interesting correlation between these and irreversible late effects (such as loss of toes); a similar mechanism, presumably affecting the vascular system, may therefore be postulated. The protective action of this well tolesated, highly effective substance, which apparently protects normal tissues from early and late injury, is discussed. (orig.) [de

Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose-Delivery and Dose-Response Study in Pigmented Hairless Mice

DEFF Research Database (Denmark)

Lerche, Catharina M; Togsverd-Bo, Katrine; Philipsen, Peter A

2017-01-01

Cumulative lifetime ultraviolet radiation (UVR) is an important factor in the development of squamous cell carcinoma. This study examines the impact of UVR exposure pattern on tumor development. Hairless C3.Cg/TifBomTac immunocompetent pigmented mice (n = 351) were irradiated with 12 standard...

Relationship between the ability of sunscreens containing 2-ethylhexyl-4'-methoxycinnamate to protect against UVR-induced inflammation, depletion of epidermal Langerhans (Ia+) cells and suppression of alloactivating capacity of murine skin in vivo.

Science.gov (United States)

Walker, S L; Morris, J; Chu, A C; Young, A R

1994-01-01

The UVB sunscreen 2-ethylhexyl-4'-methoxycinnamate was evaluated in hairless albino mouse skin for its ability to inhibit UVR-induced (i) oedema, (ii) epidermal Langerhans cell (Ia+) depletion and (iii) suppression of the alloactivating capacity of epidermal cells (mixed epidermal cell-lymphocyte reaction, MECLR). The sunscreen, prepared at 9% in ethanol or a cosmetic lotion, was applied prior to UVB/UVA irradiation. In some experiments there was a second application halfway through the irradiation. Single applications in both vehicles gave varying degrees of protection from oedema and Langerhans cell depletion but afforded no protection from suppression of MECLR. When the sunscreens were applied twice there was improved protection from oedema and Langerhans cell depletion and complete protection was afforded from suppression of MECLR. There was a clear linear relationship between Langerhans cell numbers and oedema with and without sunscreen application. The relationship between Langerhans cell numbers and MECLR was more complex. These data confirm published discrepancies between protection from oedema (a model for human erythema) and endpoints with immunological significance, but show that 2-ethylhexyl-4'-methoxycinnamate can afford complete immunoprotection, although protection is dependent on the application rate and vehicle.

Glycerol monooleate/solvents systems for progesterone transdermal delivery: In vitro permeation and microscopic studies Sistemas monoleína/solventes para a liberação transdérmica da progesterona: estudos de permeação cutânea e microscópicos

Directory of Open Access Journals (Sweden)

Gislaine R Pereira

2002-03-01

Full Text Available Transdermal delivery of most drugs is precluded by the barrier characteristics of the stratum corneum (SC. Chemical penetration enhancers are capable of interacting with SC constituents, inducing a temporary reversible increase in the skin permeability. The aim of this work was to assess the influence of glycerol monooleate (GMO/solvents systems on percutaneous absorption across hairless mouse SC of a lipophilic drug, progesterone (PG, as well as its effect on the SC structural characteristics, by scanning electron microscopy (SEM and confocal laser scanning microscopy (CLSM. The morphological changes observed in the hairless mouse SC suggest a GMO effect on the skin barrier. In addition, the increase in the In vitro PG flux and in vivo penetration of a fluorescent label point towards GMO as a potential absorption enhancer. The results obtained showed that GMO/solvents systems provoked changes in the SC that could be causing increased permeation of PG across hairless mouse skin, optimising in this way the transdermal delivery of this drug.A liberação transdérmica de muitos fármacos é dificultada pelas características de barreira do estrato córneo. Promotores químicos de absorção cutânea são capazes de interagir com os constituintes do estrato córneo, induzindo aumento temporário e reversível na permeabilidade da pele. O objetivo deste trabalho foi avaliar a influência de sistemas monoleína (monoleato de glicerol/solventes na absorção percutânea de um fármaco lipofílico (a progesterona, através do estrato córneo de camundongos sem pelo, bem como o efeito da monoleína nas características estruturais do estrato córneo, por meio de microscopia eletrônica de varredura (SEM e microscopia de varredura confocal a laser (CLSM. As alterações morfológicas observadas no estrato córneo de camundongos sem pelo sugerem efeito da monoleína na barreira da pele. E, ainda, o aumento no fluxo In vitro da progesterona, bem como na

Effects of maleimide-polyethylene glycol-modified human hemoglobin (MP4 on tissue necrosis in SKH1-hr hairless mice

Directory of Open Access Journals (Sweden)

Goertz O

2009-03-01

Full Text Available Abstract Objective Tissue hypoxia after blood loss, replantation and flap reperfusion remains a challenging task in surgery. Normovolemic hemodilution improves hemorheologic properties without increasing oxygen carrying capacity. Red blood cell transfusion is the current standard of treatment with its attendant risks. The aim of this study was to investigate the potential of the chemically modified hemoglobin, MP4, to reduce skin flap necrosis and its effect on selected blood markers and kidneys. Materials and methods Tissue ischemia was induced in the ear of hairless mice (n = 26. Hemodilution was performed by replacing one third of blood volume with the similar amount of MP4, dextran, or blood. The extent of non-perfused tissue was assessed by intravital fluorescent microscopy. Results Of all groups, MP4 showed the smallest area of no perfusion (in percentage of the ear ± SEM: 16.3% ± 2.4, the control group the largest (22.4% ± 3.5. Leukocytes showed a significant increase in the MP4 and dextran group (from 8.7 to 13.6 respectively 15.4*109/l. On histology no changes of the kidneys could be observed. Conclusion MP4 causes an increase of leukocytes, improves the oxygen supply of the tissue and shows no evidence of renal impairment.

Topical hydrocortisone, clobetasol propionate, and calcipotriol do not increase photocarcinogenesis induced by simulated solar irradiation in hairless mice

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Poulsen, Thomas

2010-01-01

topically to the backs of hairless, female, C3.Cg/TifBomTac-immunocompetent mice in 16 groups of 25 mice each. The drugs were applied three times weekly followed by 0, 2, 4, or 6 standard erythema doses (SED) of SSR for 365 days or until death. No change was observed in the time required for tumor...

BP180 dysfunction triggers spontaneous skin inflammation in mice.

Science.gov (United States)

Zhang, Yang; Hwang, Bin-Jin; Liu, Zhen; Li, Ning; Lough, Kendall; Williams, Scott E; Chen, Jinbo; Burette, Susan W; Diaz, Luis A; Su, Maureen A; Xiao, Shengxiang; Liu, Zhi

2018-06-04

BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed Δ NC16A ) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.

ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK.

Science.gov (United States)

Gao, Ge; Zhang, Tianshun; Wang, Qiushi; Reddy, Kanamata; Chen, Hanyong; Yao, Ke; Wang, Keke; Roh, Eunmiri; Zykova, Tatyana; Ma, Weiya; Ryu, Joohyun; Curiel-Lewandrowski, Clara; Alberts, David; Dickinson, Sally E; Bode, Ann M; Xing, Ying; Dong, Zigang

2017-09-01

Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the MAPK cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Mol Cancer Ther; 16(9); 1843-54. ©2017 AACR . ©2017 American Association for Cancer Research.

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

International Nuclear Information System (INIS)

Sharma, Som D.; Katiyar, Santosh K.

2010-01-01

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 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 2 production, proinflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-1β, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser 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-κB/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.

Correlation of initiating potency of skin carcinogens with potency to induce resistance to terminal differentiation in cultured mouse keratinocytes

International Nuclear Information System (INIS)

Kilkenny, A.E.; Morgan, D.; Spangler, E.F.; Yuspa, S.H.

1985-01-01

The induction by chemical carcinogens of resistance to terminal differentiation in cultured mouse keratinocytes has been proposed to represent a cellular change associated with the initiation phase of skin carcinogenesis. Previous results with this culture model indicated that the number of differentiation-resistant foci was correlated with the dose and known potency for several chemical carcinogens. Assay conditions were optimized to provide quantitative results for screening a variety of carcinogens for their potency as inducers of foci resistant to terminal differentiation. Eight skin initiators of varying potency and from different chemical classes and ultraviolet light were studied for their activity to induce this alteration in cultured epidermal cells from newborn BALB/c mice. There was an excellent positive correlation for the potency of these agents as initiators in vivo and as inducers of altered differentiation in vitro. The induction of resistant foci was independent of the relative cytotoxic effects of each agent except where cytotoxicity was extensive and reduced the number of foci. The results support the hypothesis that initiation of carcinogenesis in skin results in an alteration in the program of epidermal cell differentiation. The results also suggest that the assay is useful for identifying relative potency classes (strong, moderate, weak) of initiating agents

Chronic exposure of Sk-1 hairless mice to narrow-band ultraviolet A (320-355 nm)

International Nuclear Information System (INIS)

Menter, J.M.; Sayre, R.M.; Etemadi, A.A.; Agin, P.P.; Wills, I.

1996-01-01

Several recent investigations collectively suggest that the role of ultraviolet A (UVA) in chronic actinic skin damage may be greater than originally thought. In the present work, the output of a xenon-arc solar-simulator passed through a Bausch and Lomb monochromator in conjunction with a 2-mm Schott WG-320 filter produced narrow-band UVA centered at 338 nm, half-band width 24 nm, I 0 =3.4±0.3 mW/cm 2 . We chronically irradiated 10 SK-1 albino hairless mice 5 times per week for 18 weeks, starting with 1.25 J/cm 2 , for 33 irradiation days, sequentially followed by 1.50 J/cm 2 (34 days), 1.8 J/cm 2 (10 days), 2.0 J/cm 2 (22 days) to afford a total UVA dose of 154.3 J/cm 2 over 99 irradiation days. Erythema was noted clinically by day 6, which persisted throughout the irradiation. During the irradiation period, some scaling, consistent with mild epidermal hyperplasia was noted during irradiation days 37-56. This response later regressed despite continued chronic irradiation. Hematoxylin and eosin examination immediately after the final irradiation revealed a mild inflammatory response, with some dermal restructuring. At the end of the experiment, no significant signs of epidermal hyperplasia or (pre)malignant lesions were seen, although some stratum corneum thickening was noted. Marked dermal collagen damage and moderate elastosis was also evident. We believe that the observed differences in results reported in previous studies are in large part due to differences in light sources and irradiation protocols. (au)

Formation of thymine containing dimers in skin exposed to ultraviolet radiation

Energy Technology Data Exchange (ETDEWEB)

Johnson, B E [Dundee Univ. (UK)

1978-01-01

Nuclear DNA appears to be the major molecular target for the inhibitory, mutagenic and lethal effects of ultraviolet radiation on cells in culture. Cyclobutyl dimers between adjacent pyrimidine bases, the major photochemical lesions for these effects in prokaryotes, also play a part in UVR effects on eukaryotes cells. Pyrimidine dimers have been isolated from in vivo UV-irradiated guinea pig and mouse skin. The wavelength dependence for dimer induction is similar to that for acute skin reactions but no direct causal relationship has been established. Sunlight UVR may induce dimers in skin DNA. Excision of dimers from mouse skin in vivo is deficient as it is for most rodent cells in culture; human cell excision is efficient and the difficulties in interpretation of UV-carcinogenesis results with mice in terms of human skin cancer are therefore increased.

Novel mechanisms for the vitamin D receptor (VDR) in the skin and in skin cancer.

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Bikle, Daniel D; Oda, Yuko; Tu, Chia-Ling; Jiang, Yan

2015-04-01

The VDR acting with or without its principal ligand 1,25(OH)2D regulates two central processes in the skin, interfollicular epidermal (IFE) differentiation and hair follicle cycling (HFC). Calcium is an important co-regulator with 1,25(OH)2D at least of epidermal differentiation. Knockout of the calcium sensing receptor (CaSR) in addition to VDR accelerates the development of skin cancer in mice on a low calcium diet. Coactivators such as mediator 1 (aka DRIP205) and steroid receptor coactivator 3 (SRC3) regulate VDR function at different stages of the differentiation process, with Med 1 essential for hair follicle differentiation and early stages of epidermal differentiation and proliferation and SRC3 essential for the latter stages of differentiation including formation of the permeability barrier and innate immunity. The corepressor of VDR, hairless (HR), is essential for hair follicle cycling, although its effect on epidermal differentiation in vivo is minimal. In its regulation of HFC and IFE VDR controls two pathways-wnt/β-catenin and sonic hedgehog (SHH). In the absence of VDR these pathways are overexpressed leading to tumor formation. Whereas, VDR binding to β-catenin may block its activation of TCF/LEF1 sites, β-catenin binding to VDR may enhance its activation of VDREs. 1,25(OH)2D promotes but may not be required for these interactions. Suppression of SHH expression by VDR, on the other hand, requires 1,25(OH)2D. The major point of emphasis is that the role of VDR in the skin involves a number of novel mechanisms, both 1,25(OH)2D dependent and independent, that when disrupted interfere with IFE differentiation and HFC, predisposing to cancer formation. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Promotion of hair follicle development and trichogenesis by Wnt-10b in cultured embryonic skin and in reconstituted skin

International Nuclear Information System (INIS)

Ouji, Yukiteru; Yoshikawa, Masahide; Shiroi, Akira; Ishizaka, Shigeaki

2006-01-01

We previously showed that Wnt-10b promoted the differentiation of primary skin epithelial cells (MPSEC) toward hair shaft and inner root sheath of the hair follicle (IRS) cells in vitro. In the present study, we found that Wnt-10b promotes the development of hair follicles using a culture of mouse embryonic skin tissue and trichogenesis using a reconstitution experiment with nude mice. Hair follicle development was observed in skin taken from mouse embryos on embryonic day 10.5 following a 2-day culture with recombinant Wnt-10b (rWnt-10b), however, not without rWnt-10b. Brown hair growth was observed at the site of reconstituted skin in Balb/c nude mice where dermal fibroblasts and keratinocytes, derived from C3H/HeN new born mice, were transplanted with Wnt-10b-producing COS cells (Wnt-COS). Without the co-transplantation of Wnt-COS, no hair growth was observed. Our results suggest an important role of Wnt-10b in the initiation of hair follicle development and following trichogenesis

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

Science.gov (United States)

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.

Stable Skin-specific Overexpression of Human CTLA4-Ig in Transgenic Mice through Seven Generations

Institute of Scientific and Technical Information of China (English)

Yong WANG; Yong NI; Hong WEI; Feng-Chao WANG; Liang-Peng GE; Xiang GAO

2006-01-01

Skin graft rejection is a typical cellular immune response, mainly mediated by T cells. Cytotoxic T lymphocyte associated antigen 4-immunoglobin (CTLA4-Ig) extends graft survival by blocking the T cell co-stimulation pathway and inhibiting T cell activation. To investigate the efficacy of CTLA4-Ig in prolonging skin graft survival, human CTLA4-Ig (hCTLA4-Ig) was engineered to overexpress in mouse skin by transgenesis using the K14 promoter. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay indicated that the expression of CTLA4-Ig remained skin-specific and relatively constant compared to the internal control protein, AKT, through seven generations. The presence and concentration of the hCTLA4-Ig protein in transgenic mouse sera was determined by enzyme-linked immunosorbent assay (ELISA), and the results indicated that the serum CTLA4-Ig concentration also remained constant through generations. Survival of transgenic mouse skins grafted onto rat wounds was remarkably prolonged compared to that of wild-type skins from the same mouse strain, and remained comparable among all seven generations. This suggested that the bioactive hCTLA4-Ig protein was stably expressed in transgenical mice through at least seven generations, which was consistent with the stable skin-specific CTLA4-Ig expression.The results demonstrated that the transgenic expression of hCTLA4-Ig in skin driven by the K14 promoter remained constant through generations, and a transgenic line can be established to provide transgenic skin with extended survival reproducibly.

Molecular Mechanisms of Mouse Skin Tumor Promotion

International Nuclear Information System (INIS)

Rundhaug, Joyce E.; Fischer, Susan M.

2010-01-01

Multiple molecular mechanisms are involved in the promotion of skin carcinogenesis. Induction of sustained proliferation and epidermal hyperplasia by direct activation of mitotic signaling pathways or indirectly in response to chronic wounding and/or inflammation, or due to a block in terminal differentiation or resistance to apoptosis is necessary to allow clonal expansion of initiated cells with DNA mutations to form skin tumors. The mitotic pathways include activation of epidermal growth factor receptor and Ras/Raf/mitogen-activated protein kinase signaling. Chronic inflammation results in inflammatory cell secretion of growth factors and cytokines such as tumor necrosis factor-α and interleukins, as well as production of reactive oxygen species, all of which can stimulate proliferation. Persistent activation of these pathways leads to tumor promotion

Comparison of the carcinogenic effectiveness in mouse skin of methyl- and ethylnitrosourea, nitrosourethane and nitrosonitro-guanidine and the effect of deuterium labeling

International Nuclear Information System (INIS)

Lijinsky, W.

1982-01-01

The carcinogenic activities of a number of directly acting methylating and ethylating agents have been compared by mouse skin painting in acetone solution. Nitrosomethylurethane and nitrosoethylurethane failed to induce tumors after greater than 60 weeks treatment. Nitrosomethylurea was somewhat more effective than nitrosoethylurea, as measured by the longer latent period than nitrosoethylurea, as measured Nitrosomethylnitroguanidine, by the same measure, was a weaker carcinogen than nitrosoethylnitroguanidine at both dose levels used (0.02 M and 0.008 M); the latter compound was the most potent skin carcinogen of those examined. There was no significant difference in carcinogenic effectiveness when the alkyl group of the nitrosoureas or the nitronitrosoguanidines contained deuterium instead of hydrogen, which supports the concept that alkylation of cellular macromolecules by the intact alkyl group is responsible for carcinogenesis by these compounds

Skin-derived mesenchymal stem cells help restore function to ovaries in a premature ovarian failure mouse model.

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Dongmei Lai

Full Text Available Skin-derived mesenchymal stem cells (SMSCs can differentiate into the three embryonic germ layers. For this reason, they are considered a powerful tool for therapeutic cloning and offer new possibilities for tissue therapy. Recent studies showed that skin-derived stem cells can differentiate into cells expressing germ-cell specific markers in vitro and form oocytes in vivo. The idea that SMSCs may be suitable for the treatment of intractable diseases or traumatic tissue damage has attracted attention. To determine the ability of SMSCs to reactivate injured ovaries, a mouse model with ovaries damaged by busulfan and cyclophosphamide was developed and is described here. Female skin-derived mesenchymal stem cells (F-SMSCs and male skin-derived mesenchymal stem cells (M-SMSCs from red fluorescence protein (RFP transgenic adult mice were used to investigate the restorative effects of SMSCs on ovarian function. Significant increases in total body weight and the weight of reproductive organs were observed in the treated animals. Both F-SMSCs and M-SMSCs were shown to be capable of partially restoring fertility in chemotherapy-treated females. Immunostaining with RFP and anti-Müllerian hormone (AMH antibodies demonstrated that the grafted SMSCs survived, migrated to the recipient ovaries. After SMSCs were administered to the treated mice, real-time PCR showed that the expression levels of pro-inflammatory cytokines TNF-α, TGF-β, IL-8, IL-6, IL-1β, and IFNγ were significantly lower in the ovaries than in the untreated controls. Consistent with this observation, expression of oogenesis marker genes Nobox, Nanos3, and Lhx8 increased in ovaries of SMSCs-treated mice. These findings suggest that SMSCs may play a role within the ovarian follicle microenvironment in restoring the function of damaged ovaries and could be useful in reproductive health.

Cellularized Bilayer Pullulan-Gelatin Hydrogel for Skin Regeneration.

Science.gov (United States)

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

Xenobiotica-metabolizing enzymes in the skin of rat, mouse, pig, guinea pig, man, and in human skin models.

Science.gov (United States)

Oesch, F; Fabian, E; Landsiedel, Robert

2018-06-18

Studies on the metabolic fate of medical drugs, skin care products, cosmetics and other chemicals intentionally or accidently applied to the human skin have become increasingly important in order to ascertain pharmacological effectiveness and to avoid toxicities. The use of freshly excised human skin for experimental investigations meets with ethical and practical limitations. Hence information on xenobiotic-metabolizing enzymes (XME) in the experimental systems available for pertinent studies compared with native human skin has become crucial. This review collects available information of which-taken with great caution because of the still very limited data-the most salient points are: in the skin of all animal species and skin-derived in vitro systems considered in this review cytochrome P450 (CYP)-dependent monooxygenase activities (largely responsible for initiating xenobiotica metabolism in the organ which provides most of the xenobiotica metabolism of the mammalian organism, the liver) are very low to undetectable. Quite likely other oxidative enzymes [e.g. flavin monooxygenase, COX (cooxidation by prostaglandin synthase)] will turn out to be much more important for the oxidative xenobiotic metabolism in the skin. Moreover, conjugating enzyme activities such as glutathione transferases and glucuronosyltransferases are much higher than the oxidative CYP activities. Since these conjugating enzymes are predominantly detoxifying, the skin appears to be predominantly protected against CYP-generated reactive metabolites. The following recommendations for the use of experimental animal species or human skin in vitro models may tentatively be derived from the information available to date: for dermal absorption and for skin irritation esterase activity is of special importance which in pig skin, some human cell lines and reconstructed skin models appears reasonably close to native human skin. With respect to genotoxicity and sensitization reactive

Transdermal therapeutic system of narcotic analgesics using nonporous membrane (I) : Effect of the ethanol permeability on vinylacetate content of EVA membrane

Energy Technology Data Exchange (ETDEWEB)

Kwon, H.; Song, H.Y. [Chungnam National University, Taejon (Korea); Khang, G.S. [Chonbuk National University, Chonju (Korea); Lee, H.B. [Korea Research Institute of Chemical Technology, Taejon (Korea)

1999-05-01

The fundamental properties of transdermal therapeutic patch as narcotic analgesics agent has been investigated. From the study of drug and ethanol release patterns from the fentanyl base (FB) patches through diffusion cell and hairless mouse skin, it was observed that the FB release patterns were largely affected by the content of vinyl acetate (VA) of ethylene-co-vinyl acetate (EVA) membrane, and volume fraction of ethanolic solution. Additionally, a variety of control membrane as a function of VA content were examined for swelling following equilibration with ethanolic solutions. Generally, ethanol was incorporated into a transdermal therapeutic device to enable the controlled delivery of enhancer and drug to the skin surface. In vitro skin permeation analysis of the control membrane showed that ethanol flux was linearly related to the ethanol volume fraction. This result was shown that drug permeability increased with increasing as the content of VA. But, the FB flux from saturated aqueous ethanol solutions increases until 80% ethanol volume fraction. Over 80% ethanol volume fraction, the FB flux through skin samples is independent of ethanol volume. These results showed that the decrease in skin permeation due to dehydration nis the dominant effect. 26 refs., 8 figs.

Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes

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Tianzhi Chen

2016-09-01

Full Text Available To investigate whether ocular albinism type 1 (OA1 is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR, immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes’ pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF, tyrosinase (TYR, tyrosinase-related protein 1 (TRP1 and premelanosome protein (PMEL. However, the tyrosinase-related protein 2 (TRP2 level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may

Loss of Endogenous Interleukin-12 Activates Survival Signals in Ultraviolet-Exposed Mouse Skin and Skin Tumors

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Syed M. Meeran

2009-09-01

Full Text Available Interleukin-12 (IL-12-deficiency promotes photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Here, we report that long-term exposure to ultraviolet (UV radiation resulted in enhancement of the levels of cell survival kinases, such as phosphatidylinositol 3-kinase (PI3K, Akt (Ser473, p-ERK1/2, and p-p38 in the skin of IL-12p40 knockout (IL-12 KO mice compared with the skin of wild-type mice. UV-induced activation of nuclear factor-κB (NF-κB/p65 in the skin of IL-12 KO mice was also more prominent. The levels of NF-κB-targeted proteins, such as proliferating cell nuclear antigen (PCNA, cyclooxygenase-2, cyclin D1, and inducible nitric oxide synthase, were higher in the UV-exposed skin of IL-12 KO mice than the UV-exposed skin of wild types. In short-term UV irradiation experiments, subcutaneous treatment of IL-12 KO mice with recombinant IL-12 (rIL-12 or topical treatment with oridonin, an inhibitor of NF-κB, resulted in the inhibition of UV-induced increases in the levels of PCNA, cyclin D1, and NF-κB compared with non-rIL-12- or non-oridonin-treated IL-12 KO mice. UV-induced skin tumors of IL-12 KO mice had higher levels of PI3K, p-Akt (Ser473, p-ERK1/2, p-p38, NF-κB, and PCNA and fewer apoptotic cells than skin tumors of wild types. Together, these data suggest that the loss of endogenous IL-12 activates survival signals in UV-exposed skin and that may lead to the enhanced photocarcinogenesis in mice.

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

Energy Technology Data Exchange (ETDEWEB)

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.

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

International Nuclear Information System (INIS)

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

1983-01-01

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: [ 3 H]thymidine incorporation decreased by 80% and [ 14 C]leucine incorporation by 44% as compared with the UVB-irradiated control mice. A slight decrease in the ratio of [ 3 H]histidine/[ 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

Evaluation of Permacol as a cultured skin equivalent.

Science.gov (United States)

MacLeod, T M; Cambrey, A; Williams, G; Sanders, R; Green, C J

2008-12-01

Skin loss following severe burn requires prompt wound closure to avoid such complications as fluid and electrolyte imbalance, infection, immune suppression, and pain. In clinical situations in which insufficient donor skin is available, the development of cultured skin equivalents (dermal matrices seeded with keratinocytes and fibroblasts) may provide a useful alternative. The aim of this study was to assess the suitability of a porcine-derived dermal collagen matrix (Permacol) to function as a cultured skin equivalent in supporting the growth of keratinocytes in vitro and providing cover to full thickness wounds in the BALB C/nude mouse model. A histological comparison was against Glycerol treated-Ethylene Oxide Sterilised Porcine Dermis (Gly-EO Dermis) which has successfully been used as a cultured skin equivalent in previous studies. Both Gly-EO Dermis and to a lesser extent Permacol were able to support the growth of cultured keratinocytes following a 16-day period of cell culture, however, this study was only able to demonstrate the presence of an epidermal layer on Gly-EO dermis 2 weeks after grafting onto full-thickness wounds in the BALB C/nude mouse model.

Development of Lecithin Nanoemulsion Based Organogels for Permeation Enhancement of Metoprolol through Rat Skin

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J. Varshosaz

2013-01-01

Full Text Available Background. Drugs with low oral bioavailability due to the first pass metabolism are good candidates for transdermal delivery. Objectives. The aim of this work was preparation of transdermal nanoemulsion of metoprolol which has high first pass metabolism. Methods. Three commercially available types of lecithin (200, 100p, and 170, three short chain alcohol (n-butanol, isopropyl alcohol, and n-propanol, and isopropyl myristate (IPM were used as surfactant, cosurfactant, and oil phase, respectively. The aqueous phase was composed of metoprolol tartrate. Nanoemulsions with different surfactant/cosurfactant weight ratio, various amounts of drug, and different types of alcohol were prepared, and their phase diagrams were studied. Drug release, permeability, and diffusion coefficient of the drug were studied using hairless rat skin. Results. A significant increase in drug solution rate was observed with increasing the metoprolol content in the nanoemulsions, while it decreased when lecithin concentration increased from 40% to 60%. Increasing the water content resulted in a significant increase in metoprolol release. N-butanol enhanced the drug flux from nanoemulsions more than n-propanol and isopropyl alcohol. The o/w nanoemulsions of metoprolol showed high flux and permeability through the skin. Conclusion. Both w/o and o/w nanoemulsions of metoprolol could enhance permeation and diffusion of metoprolol through rat skin.

Injected Hyaluronidase Reduces the Volume of Exogenous Hyaluronate Fillers in Mice and Results in Clinical Improvement in a Patient with Pretibial Myxedema

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Sébastien Menzinger

2016-07-01

Full Text Available Background: Hyaluronidases are essential for the breakdown of hyaluronate (HA in tissues and may be used to prevent the adverse effects of HA fillers. Objectives: We explored the effect of hyaluronidase on exogenous and endogenous HA in vitro and in vivo. Materials and Methods: HA fillers were incubated with different concentrations of hyaluronidase and visualized by electrophoresis. HA fillers were injected in the skin of hairless mice, and 4 h later hyaluronidase was injected in the papules of exogenous HA. Hyaluronidase was injected in the nodule of pretibial myxedema of a male patient with Graves' disease. Skin sections of mice and of the patient were performed, and a skin ultrasound system was used to monitor the evolution of skin lesions. Results: Hyaluronidase showed a degrading effect on HA with increasing concentrations. Hyaluronidase injection significantly decreased the content of exogenous HA within 3 days. Intralesional injection of hyaluronidase resulted in dissolution of the nodule of pretibial myxedema with no recurrence during 3 months. Conclusion. These results show that the injection of hyaluronidase is capable of degrading exogenous HA in mouse skin and endogenous HA in human skin in vivo and may be a therapeutic option for skin diseases characterized by abnormal accumulation of HA.

Influence of misonidazole, anaesthesia, clamping of the leg and stress of the animal during treatment on the radiation-induced skin reaction of mouse feet

International Nuclear Information System (INIS)

Wondergem, J.; Haveman, J.; Schueren, E. van der

1982-01-01

The influence of anaesthesia and misonidazole on the 'acute' (average of the scores between day 10 and 30) and 'late' (average of the scores between day 100 and 120) skin reaction of the feet of mice was investigated under two different conditions. Firstly, the legs were kept untaped in the radiation field; secondly, the legs were fixed with surgical tape on the backscatter block. Irradiation was carried out by X-radiation at a dose of 35 Gy. Results showed that stress in unanaesthetized animals has a large influence on the radiation response of mouse skin. Adequate treatment conditions, tranquillizers or anaesthesia can compensate for this factor. Taping of the animals' legs, resulting in clamping, interferes with the assessment of these modalities. No influence of misonidazole on the skin reaction could be demonstrated in conditions where no artificial hypoxia was induced. The importance of taking experimental conditions into account is pointed out for the correct assessment of the effect of radiosensitizers and possibly other anticancer drugs. (U.K.)

Quantitatively characterizing microstructural variations of skin tissues during ultraviolet radiation damaging process based on Mueller matrix polarimetry

Science.gov (United States)

Sheng, Wei; He, Honghui; Dong, Yang; Ma, Hui

2018-02-01

As one of the most fundamental features of light, polarization can be used to develop imaging techniques which can provide insight into the optical and structural properties of tissues. Especially, the Mueller matrix polarimetry is suitable to detect the changes in collagen and elastic fibres, which are the main compositions of skin tissue. Here we demonstrate a novel quantitative, non-contact and in situ technique to monitor the microstructural variations of skin tissue during ultraviolet radiation (UVR) induced photoaging based on Mueller matrix polarimetry. Specifically, we measure the twodimensional (2D) backscattering Mueller matrices of nude mouse skin samples, then calculate and analyze the Mueller matrix derived parameters during the skin photoaging and self-repairing processes. To induce three-day skin photoaging, the back skin of each mouse is irradiated with UVR (0.05J/cm2) for five minutes per day. After UVR, the microstructures of the nude mouse skin are damaged. During the process of UV damage, we measure the backscattering Mueller matrices of the mouse skin samples and examine the relationship between the Mueller matrix parameters and the microstructural variations of skin tissue quantitatively. The comparisons between the UVR damaged groups with and without sunscreens show that the Mueller matrix derived parameters are potential indicators for fibrous microstructure variation in skin tissue. The pathological examinations and Monte Carlo simulations confirm the relationship between the values of Mueller matrix parameters and the changes of fibrous structures. Combined with smart phones or wearable devices, this technique may have a good application prospect in the fields of cosmetics and dermatological health.

Folate deficiency enhances arsenic effects on expression of genes involved in epidermal differentiation in transgenic K6/ODC mouse skin

International Nuclear Information System (INIS)

Nelson, Gail M.; Ahlborn, Gene J.; Delker, Don A.; Kitchin, Kirk T.; O'Brien, Thomas G.; Chen Yan; Kohan, Michael J.; Roop, Barbara C.; Ward, William O.; Allen, James W.

2007-01-01

Chronic arsenic exposure in humans is associated with cancers of the skin, lung, bladder and other tissues. There is evidence that folate deficiency may increase susceptibility to arsenic effects, including skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm sodium arsenite for 5 months. In the current study, K6/ODC mice maintained on either a folate deficient or folate sufficient diet were exposed to 0, 1, or 10 ppm sodium arsenite in the drinking water for 30 days. Total RNA was isolated from skin samples and gene expression analyzed using Affymetrix Mouse 430 2.0 GeneChips. Data from 24 samples, with 4 mice in each of the 6 treatment groups, were RMA normalized and analyzed by two-way ANOVA using GeneSpring TM . Top gene ontology (GO) categories for genes responding significantly to both arsenic treatment and folate deficiency include nucleotide metabolism and cell organization and biogenesis. For many of these genes, folate deficiency magnifies the response to arsenic treatment. In particular, expression of markers of epidermal differentiation, e.g., loricrin, small proline rich proteins and involucrin, was significantly reduced by arsenic in the folate sufficient animals, and reduced further or at a lower arsenic dose in the folate deficient animals. In addition, expression of a number of epidermal cell growth/proliferation genes and cellular movement genes was altered. These results indicate that arsenic disrupts the normal balance of cell proliferation and differentiation, and that folate deficiency exacerbates these effects, consistent with the view that folate deficiency is a nutritional susceptibility factor for arsenic-induced skin tumorigenesis

Radiation-induced skin injury in the animal model of scleroderma: implications for post-radiotherapy fibrosis

International Nuclear Information System (INIS)

Kumar, Sanath; Kolozsvary, Andrew; Kohl, Robert; Lu, Mei; Brown, Stephen; Kim, Jae Ho

2008-01-01

Radiation therapy is generally contraindicated for cancer patients with collagen vascular diseases (CVD) such as scleroderma due to an increased risk of fibrosis. The tight skin (TSK) mouse has skin which, in some respects, mimics that of patients with scleroderma. The skin radiation response of TSK mice has not been previously reported. If TSK mice are shown to have radiation sensitive skin, they may prove to be a useful model to examine the mechanisms underlying skin radiation injury, protection, mitigation and treatment. The hind limbs of TSK and parental control C57BL/6 mice received a radiation exposure sufficient to cause approximately the same level of acute injury. Endpoints included skin damage scored using a non-linear, semi-quantitative scale and tissue fibrosis assessed by measuring passive leg extension. In addition, TGF-β1 cytokine levels were measured monthly in skin tissue. Contrary to our expectations, TSK mice were more resistant (i.e. 20%) to radiation than parental control mice. Although acute skin reactions were similar in both mouse strains, radiation injury in TSK mice continued to decrease with time such that several months after radiation there was significantly less skin damage and leg contraction compared to C57BL/6 mice (p < 0.05). Consistent with the expected association of transforming growth factor beta-1 (TGF-β1) with late tissue injury, levels of the cytokine were significantly higher in the skin of the C57BL/6 mouse compared to TSK mouse at all time points (p < 0.05). TSK mice are not recommended as a model of scleroderma involving radiation injury. The genetic and molecular basis for reduced radiation injury observed in TSK mice warrants further investigation particularly to identify mechanisms capable of reducing tissue fibrosis after radiation injury

Recovery Effects of Oral Administration of Glucosylceramide and Beet Extract on Skin Barrier Destruction by UVB in Hairless Mice

Directory of Open Access Journals (Sweden)

Yoshihiro Tokudome

2017-10-01

Full Text Available Purified glucosylceramide from beet extract (beet GlcCer and beet extract containing an equal amount of GlcCer were administered orally to ultra violet B (UVB-irradiated mice, and differences in the protective effects against skin barrier dysfunction caused by UVB irradiation were compared. In the beet GlcCer group, epidermal thickening and the decrease in stratum corneum (SC ceramide content caused by UVB irradiation were reduced. In the group that was orally administered beet extract containing glucosylceramide, effects similar to those in the beet GlcCer group were observed. Oral administration of beet GlcCer had no obvious effects against an increase in TEWL or decrease in SC water content after UVB irradiation, but there was improvement in the beet extract group. Oral administration of beet GlcCer is effective in improving skin barrier function in UVB-irradiated mice. Beet extract contains constituents other than GlcCer that are also effective in improving skin barrier function.

Innate lymphoid cells and the skin

OpenAIRE

Salimi, Maryam; Ogg, Graham

2014-01-01

Innate lymphoid cells are an emerging family of effector cells that contribute to lymphoid organogenesis, metabolism, tissue remodelling and protection against infections. They maintain homeostatic immunity at barrier surfaces such as lung, skin and gut (Nature 464:1367?1371, 2010, Nat Rev Immunol 13: 145?149, 2013). Several human and mouse studies suggest a role for innate lymphoid cells in inflammatory skin conditions including atopic eczema and psoriasis. Here we review the innate lymphoid...

Differential tumor biology effects of double-initiation in a mouse skin chemical carcinogenesis model comparing wild type versus protein kinase Cepsilon overexpression mice.

Science.gov (United States)

Li, Yafan; Wheeler, Deric L; Ananthaswamy, Honnavara N; Verma, Ajit K; Oberley, Terry D

2007-12-01

Our previous studies showed that protein kinase Cepsilon (PKCepsilon) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma formation as is typically observed in wild type mice. The present study demonstrates that double-DMBA initiation modulates tumor incidence, multiplicity, and latency period in both wild type and PKCepsilon overexpression transgenic (PKCepsilon-Tg) mice. After 17 weeks (wks) of tumor promotion, a reduction in papilloma multiplicity was observed in double- versus single-DMBA initiated wild type mice. Papilloma multiplicity was inversely correlated with cell death indices of interfollicular keratinocytes, indicating decreased papilloma formation was caused by increased cell death and suggesting the origin of papillomas is in interfollicular epidermis. Double-initiated PKCepsilon-Tg mice had accelerated carcinoma formation and cancer incidence in comparison to single-initiated PKCepsilon-Tg mice. Morphologic analysis of mouse skin following double initiation and tumor promotion showed a similar if not identical series of events to those previously observed following single initiation and tumor promotion: putative preneoplastic cells were observed arising from hyperplastic hair follicles (HFs) with subsequent cancer cell infiltration into the dermis. Single-initiated PKCepsilon-Tg mice exhibited increased mitosis in epidermal cells of HFs during tumor promotion.

The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

Directory of Open Access Journals (Sweden)

Youssef W. Naguib

2014-02-01

Full Text Available 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.

Experimental studies of radiation carcinogenesis in the skin: a review

International Nuclear Information System (INIS)

Coggle, J.E.; Williams, J.P.

1990-01-01

Dose and time response characteristics of cancer induction following a variety of modes and qualities of radiation exposure are reviewed in relation to rat and mouse skin studies. Despite interspecies differences, it is shown that all of the experimental data for radiogenic skin cancer, when expressed per unit area of skin, fall on a relatively narrow and well defined response curve, which is approximately two orders of magnitude more sensitive than the human skin cancer dose response. (UK)

Assessment of the potential skin irritation of lysine-derivative anionic surfactants using mouse fibroblast and human keratinocytes as an alternative to animal testing

OpenAIRE

Sánchez Molina, Lourdes; Mitjans Arnal, Montserrat; Infante Martínez-Pardo, Ma. Rosa; Vinardell Martínez-Hidalgo, Ma. Pilar

2004-01-01

Purpose. The aim of this study was to identify new surfactants with low skin irritant properties for use in pharmaceutical and cosmetic formulations, employing cell culture as an alternative method to in vivo testing. In addition, we sought to establish whether potential cytotoxic properties were related to the size of the counterions bound to the surfactants. Methods. Cytotoxicity was assessed in the mouse fibroblast cell line 3T6, and the human keratinocyte cell line NCTC 2544, using the MT...

[Effect of dibunol liniment on posttraumatic skin regeneration in mice].

Science.gov (United States)

Krutova, T V; Efimov, E A; Korman, D B

1984-10-01

The effect of dibunol liniment (5-50 mg/kg) on excised mouse skin was studied. The liniment caused complete skin regeneration with hair and gland formation in the majority of treated mice. Application of the liniment led to a considerable increase in proliferative activity of skin epithelial cells and inhibition of wound area reduction within the first day of healing as compared with controls.

Anti-ageing effects of a new synthetic sphingolipid (K6EAA-L12) on aged murine skin.

Science.gov (United States)

Jung, Minyoung; Lee, Sanghoon; Park, Hwa-young; Youm, Jong-Kyung; Jeong, Sekyoo; Bae, Jonghwan; Kwon, Mi Jung; Park, Byeong Deog; Lee, Seung Hun; Choi, Eung Ho

2011-04-01

Recently, we reported on the anti-ageing effects of K6PC-5. This compound induced keratinocyte differentiation and fibroblast proliferation by increasing sphingosine-1 phosphate synthesis. We performed this study to confirm the anti-ageing effects of new synthetic products (the K6EAA series) derived from K6PC-5 through an amino group induction. Cellular responses such as differentiation, proliferation and calcium mobilization were investigated using cultured human keratinocytes and fibroblasts. Also, we measured the expressions of collagen mRNA and protein using real time RT-PCR and ELISA, respectively. The K6EAA-L12 product, selected by in vitro screening, was evaluated for anti-ageing effects on intrinsically and extrinsically (photo) aged models of hairless mice. In the intrinsically aged murine skin, K6EAA-L12 showed anti-ageing effects by activating collagen synthesis, eventually causing dermal thickening. Also, in the photo-aged skin, the dermal collagen density and dermal thickness were increased. In photo-aged murine skin, K6EAA-L12 increased stratum corneum integrity by increasing corneodesmosome density and improved the barrier recovery rate. However, there were no changes in the expressions of epidermal differentiation maker proteins. In conclusion, topical K6EAA-L12, a new synthetic K6PC-5 derivative, improves intrinsically and extrinsically (photo) aged skin by increasing the collagen density and improving the skin barrier function. © 2011 John Wiley & Sons A/S.

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

Science.gov (United States)

1985-09-01

methyl nitrosourea on mouse skin in the drop test. Acta Biol. Med. Ger. 16: KI-K3. Hennings, H., and R. K. Boutwel’.. 1969. Inhibition of DNA synthesis ...J., G. T. Bowden, B. G. Shapas, and R. K. Boutwell. 1973. "Macromolecular synthesis following a single application of alkylating agents used as

Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice.

Science.gov (United States)

Reeve, Vivienne E; Domanski, Diane; Slater, Michael

2006-01-01

In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.

Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure

DEFF Research Database (Denmark)

Maccarana, Marco; Svensson, René B; Knutsson, Anki

2017-01-01

SLRPs is asporin. Here we describe the successful generation of an Aspn-/- mouse model and the investigation of the Aspn-/- skin phenotype. Functionally, Aspn-/- mice had an increased skin mechanical toughness, although there were no structural changes present on histology or immunohistochemistry......) was downregulated. Intriguingly no differences were observed in collagen protein content or in collagen cross-linking-related lysine oxidation or hydroxylation. The glycosaminoglycan content and structure in Aspn-/- skin was profoundly altered: chondroitin/dermatan sulfate was more than doubled and had an altered......The main structural component of connective tissues is fibrillar, cross-linked collagen whose fibrillogenesis can be modulated by Small Leucine-Rich Proteins/Proteoglycans (SLRPs). Not all SLRPs' effects on collagen and extracellular matrix in vivo have been elucidated; one of the less investigated...

Anti-aging effect of adipose-derived stem cells in a mouse model of skin aging induced by D-galactose.

Directory of Open Access Journals (Sweden)

Shengchang Zhang

Full Text Available INTRODUCTION: Glycation products accumulate during aging of slowly renewing tissue, including skin, and are suggested as an important mechanism underlying the skin aging process. Adipose-derived cells are widely used in the clinic to treat ischemic diseases and enhance wound healing. Interestingly, adipose-derived stem cells (ASCs are also effective in anti-aging therapy, although the mechanism underlying their effects remains unknown. The purpose of the present study was to examine the anti-aging effect of ASCs in a D-galactose-induced aging animal model and to clarify the underlying mechanism. MATERIALS AND METHODS: Six-week-old nude mice were subcutaneously injected with D-gal daily for 8 weeks. Two weeks after completion of treatment, mice were randomized to receive subcutaneous injections of 106 green fluorescent protein (GFP-expressing ASCs, aminoguanidine (AG or phosphate-buffered saline (PBS. Control mice received no treatment. We examined tissue histology and determined the activity of senescence-associated molecular markers such as superoxide dismutase (SOD and malondialdehyde (MDA. RESULTS: Transplanted ASCs were detectable for 14 days and their GFP signal disappeared at day 28 after injection. ASCs inhibited advanced glycation end product (AGE levels in our animal model as well as increased the SOD level and decreased the MDA level, all of which act to reverse the aging phenotype in a similar way to AG, an inhibitor of AGE formation. Furthermore, ASCs released angiogenic factors in vivo such as vascular endothelial growth factor, suggesting a skin trophic effect. CONCLUSIONS: These results demonstrate that ASCs may contribute to the regeneration of skin during aging. In addition, the data shows that ASCs provide a functional benefit by glycation suppression, antioxidation, and trophic effects in a mouse model of aging.

Mouse allergen-specific immunoglobulin G4 and risk of mouse skin test sensitivity

NARCIS (Netherlands)

Matsui, E. C.; Diette, G. B.; Krop, E. J. M.; Aalberse, R. C.; Smith, A. L.; Eggleston, P. A.

2006-01-01

High serum levels of cat-specific IgG and IgG4 are associated with protection against allergic sensitization to cat, but whether this association applies to other animal allergens remains unclear. To determine if high levels of mouse-specific IgG and IgG4 are associated with a decreased risk of

Diclofenac enables prolonged delivery of naltrexone through microneedle-treated skin.

Science.gov (United States)

Banks, Stan L; Paudel, Kalpana S; Brogden, Nicole K; Loftin, Charles D; Stinchcomb, Audra L

2011-05-01

The purpose of this study was to determine if non-specific COX inhibition could extend pore lifetime in hairless guinea pigs following microneedle treatment. Hairless guinea pigs were treated with microneedle arrays ± daily application of Solaraze® gel (3% diclofenac sodium (non-specific COX inhibitor) and 2.5% hyaluronic acid); transepidermal water loss was utilized to evaluate pore lifetime. To examine the permeation of naltrexone, additional guinea pigs were treated with microneedles ± daily Solaraze® gel followed by application of a 16% transdermal naltrexone patch; pharmacokinetic analysis of plasma naltrexone levels was performed. Histological analysis was employed to visualize morphological changes following microneedle and Solaraze® treatment. Animals treated with microneedles + Solaraze® displayed extended pore lifetime (determined by transepidermal water loss measurements) for up to 7 days. Enhanced naltrexone permeation was also observed for an extended amount of time in animals treated with microneedles + Solaraze®. No morphological changes resulting from microneedle treatment or COX inhibition were noted. Non-specific COX inhibition is an effective means of extending pore lifetime following microneedle treatment in hairless guinea pigs. This may have clinical implications for extending transdermal patch wear time and therefore increasing patient compliance with therapy.

Treating cutaneous squamous cell carcinoma using ALA PLGA nanoparticle-mediated photodynamic therapy in a mouse model

Science.gov (United States)

Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Wang, Xiuli; Zhao, Feng; Luan, Hansen

2015-03-01

Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted ALA delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Methods: UV-induced cutaneous SCCs were established in hairless mice. ALA loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NPs-induced protoporphyrin IX (PpIX) fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results: PLGA NPs could enhance PpIX production in SCC. ALA PLGA NP mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC.

Acute skin lesions following psoralen plus ultraviolet A radiation investigated by optical coherence tomography

International Nuclear Information System (INIS)

Liu, Z M; Zhong, H Q; Zhai, J; Wang, C X; Xiong, H L; Guo, Z Y

2013-01-01

Psoralen plus ultraviolet A radiation (PUVA) therapy is a very important clinical treatment of skin diseases such as vitiligo and psoriasis, but associated with an increased risk of skin photodamage, especially photoaging. In this work, optical coherence tomography (OCT), a novel non-invasive imaging technology, was introduced to investigate in vivo the photodamage induced by PUVA qualitatively and quantitatively. Balb/c mouse dorsal skin was treated with 8-methoxypsoralen (8-MOP), and then exposed to UVA radiation. OCT images of the tissues were obtained by an OCT system with a 1310 nm central wavelength. Skin thickness and the attenuation coefficient were extracted from the OCT images to analyze the degree of injury to mouse skin. The results demonstrated that PUVA-treated skin showed an increase in skin thickness, and a reduction of attenuation coefficient in the OCT signal compared with the control groups. The data also showed good correlation with the results observed in histological sections using hematoxylin and eosin staining. In conclusion, OCT is a promising tool for photobiological studies aimed at assessing the effect of PUVA therapy in vivo. (paper)

Contribution to the penetration of radionuclides across the skin

International Nuclear Information System (INIS)

Koprda, V.; Harangozo, M.; Kassai, Z.

2000-01-01

The human skin as well as the skin of animal species represent a strong barrier against the permeation of ionic forms of substances into an organism. Radionuclides of cesium, cobalt and actinides belong to frequent potential contaminants of human body at an accidental radioactive contamination. Regarding the actual composition of contaminating mixture of radionuclides the damage of an organism after internal contamination is proportional to the extent of penetrated amounts of radionuclides across the skin. In this paper: the time dependence of permeation of 137 Cs + , 60 Co 2+ , and 147 Pm 3+ from aqueous solution through animal skin model was studied, the biologic structure mostly responsible for the barrier effect was selected and proved, the relative importance of the main diffusion pathways for 137 Cs + , 60 Co 2+ and 147 Pm 3+ , the diffusion across the intact skin and the diffusion through the hair channels was assessed, the effect of isotopic carrier on the penetration process was studied, and the retarding capacities of different substances were researched. In all experiments the radioactive tracers were used. The experimental arrangement consisted of Franz-type vertical permeation cells. The well standardized animal skin models were chosen: fresh skin from abdominal region of 5 day old rats (5DR) of Wistar strain (Breeding Farm Dobra Voda, SK) and 9 day old rats (9DR), resp.. The skins of 5DR are still hairless, and 9DR are just short haired. The 5DR skin was used intact, and also with decreasing thickness of horny layer after it had been stripped with Scotch type (3M) 5-20 times respectively, or the skin had been splitted in 60degC hot water, whereby the whole epidermis was removed. Ions penetrated in vitro through the skin from donor solution (vehicle water) to receptor solution (phosphate buffered saline), were determined in aliquots sampled in 1,3,5,7 a 24 hours. The penetrated amounts of ions were found proportional to the time at least in the first 7

Communication Framework For the Mionix Naos QG Mouse

DEFF Research Database (Denmark)

Wulff-Jensen, Andreas

2017-01-01

The Mionix Naos QG mouse has multiple sensors integrated. It can record all the metrics native to mice: being scroll, clicks and mouse movements. Moreover, this mouse has heart rate (HR) and Galvanic Skin Response (GSR) sensors embedded. Through Mionics API [1] WebSocket can be used to access all...... or be recorded. Another Unity implementation have been developed as well. This was directly connected to the WebSocket, and has the same properties as the first Unity development. Since two nearly identical implementations were made, the quality of their recordings and data communication were tested. Based...

Formulation and in vitro/in vivo evaluation of chitosan-based film forming gel containing ketoprofen.

Science.gov (United States)

Oh, Dong-Won; Kang, Ji-Hyun; Lee, Hyo-Jung; Han, Sang-Duk; Kang, Min-Hyung; Kwon, Yie-Hyuk; Jun, Joon-Ho; Kim, Dong-Wook; Rhee, Yun-Seok; Kim, Ju-Young; Park, Eun-Seok; Park, Chung-Woong

2017-11-01

The film forming gel, adhered to skin surfaces upon application and formed a film, has an advantage onto skin to provide protection and continuous drug release to the application site. This study aimed to prepare a chitosan-based film forming gel containing ketoprofen (CbFG) and to evaluate the CbFG and film from CbFG (CbFG-film). CbFG were prepared with chitosan, lactic acid and various skin permeation enhancers. The physicochemical characteristics were evaluated by texture analysis, viscometry, SEM, DSC, XRD and FT-IR. To identify the mechanism of skin permeation, in vitro skin permeation study was conducted with a Franz diffusion cell and excised SD-rat and hairless mouse dorsal skin. In vivo efficacy assessment in mono-iodoacetate (MIA)-induced rheumatoid arthritis animal model was also conducted. CbFG was successfully prepared and, after applying CbFG to the excised rat dorsal skin, the CbFG-film was also formed well. The physicochemical characteristics of CbFG and CbFG-film could be explained by the grafting of oleic acid onto chitosan in the absence of catalysts. In addition, CbFG containing oleic acid had a higher skin permeation rate in comparison with any other candidate enhancers. The in vivo efficacy study also confirmed significant anti-inflammatory and analgesic effects. Consequently, we report the successful preparation of chitosan-based film forming gel containing ketoprofen with excellent mechanical properties, skin permeation and anti-inflammatory and analgesic effects.

Wrist Hypothermia Related to Continuous Work with a Computer Mouse: A Digital Infrared Imaging Pilot Study

Directory of Open Access Journals (Sweden)

Jelena Reste

2015-08-01

Full Text Available 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.

D-aspartic acid in aged mouse skin and lens

International Nuclear Information System (INIS)

Fujii, Noriko; Muraoka, Shiro; Harada, Kaoru; Tamanoi, Itsuro; Joshima, Hisamasa; Kashima, Masatoshi.

1987-01-01

D-aspartic acid (D-Asp) was detected in the skin and lens from naturally aged mice. An analysis of the amino acid composition indicated that D-Asp did not derive from collagen. An immunological analysis using Oucterlony's agar diffusion method also confirmed that the protein containing D-Asp was not a serum protein. The process producing D-Asp is regarded as one other than racemization because the life span of mice is not long enough to permit D-Asp by racemization. Continuous low-dose-rate gamma-irradiation (37R per day) for 102 to 112 days did not increase significantly the amount of D-Asp in skin and lens of mice. (author)

A Mouse Model of Hyperproliferative Human Epithelium Validated by Keratin Profiling Shows an Aberrant Cytoskeletal Response to Injury

Directory of Open Access Journals (Sweden)

Samal Zhussupbekova

2016-07-01

Full Text Available A validated animal model would assist with research on the immunological consequences of the chronic expression of stress keratins KRT6, KRT16, and KRT17, as observed in human pre-malignant hyperproliferative epithelium. Here we examine keratin gene expression profile in skin from mice expressing the E7 oncoprotein of HPV16 (K14E7 demonstrating persistently hyperproliferative epithelium, in nontransgenic mouse skin, and in hyperproliferative actinic keratosis lesions from human skin. We demonstrate that K14E7 mouse skin overexpresses stress keratins in a similar manner to human actinic keratoses, that overexpression is a consequence of epithelial hyperproliferation induced by E7, and that overexpression further increases in response to injury. As stress keratins modify local immunity and epithelial cell function and differentiation, the K14E7 mouse model should permit study of how continued overexpression of stress keratins impacts on epithelial tumor development and on local innate and adaptive immunity.

Lactobacillus salivarius LA307 and Lactobacillus rhamnosus LA305 attenuate skin inflammation in mice.

Science.gov (United States)

Holowacz, S; Blondeau, C; Guinobert, I; Guilbot, A; Hidalgo, S; Bisson, J F

2018-02-27

Oral probiotics potential for the management of dermatological diseases is vast. However, results of available studies in skin diseases, such as atopic dermatitis (AD), are inconsistent, partly because probiotic effects are strain specific. Careful selection of probiotic strains is therefore indispensable to ensure efficacy of treatment. In this study, Lactobacillus salivarius LA307, Lactobacillus rhamnosus LA305 and Bifidobacterium bifidum PI22, three strains that were previously identified for their interesting immunomodulatory properties in allergy and/or colitis models, were assessed in the prevention of chronic skin inflammation induced by repeated applications of 12-O-tetradecanoylphorbol-13-acetate in hairless SKH-1 mice. Macroscopic and microscopic evaluation of skin lesions was performed together with measurements of serum levels of interleukin (IL)-1β, IL-6, tumour necrosis factor alpha (TNF-α), IL-17, IL-22, IL-10 and IL-4. Daily oral treatment with the three strains at the dose of 1×10 9 cfu/day for 3 weeks limited the development of chronic skin inflammation, the effects being strain dependent. Indeed the two Lactobacillus strains significantly limited the intensity of skin inflammation both at the macroscopic and microscopic levels. Macroscopic observations were correlated to the histological observations and the resulting microscopic score. This limitation of the development of AD-like skin lesions involved the modulation of cytokine production. Treatment with the two Lactobacillus strains induced a decrease in the serum levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, IL-17, IL-22 and at the opposite an increase in the production of the anti-inflammatory cytokine IL-10 and also of IL-4. Globally, B. bifidum PI22 had lower benefits. These results obtained in mice suggest that L. salivarius LA307 and L. rhamnosus LA305 could be good candidates for preserving skin integrity and homeostasis via the modulation of the gut microbiota and that

Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin and systemic toxicity

International Nuclear Information System (INIS)

Tewari-Singh, Neera; Goswami, Dinesh G; Kant, Rama; Croutch, Claire R; Casillas, Robert P; Orlicky, David J; Agarwal, Rajesh

2017-01-01

Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8 h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFα levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury. - Highlights: • Phosgene oxime cutaneous exposure causes skin blanching, edema and urticaria. • Penetration of phosgene oxime causes dilation of vasculature in internal organs. • Mast cells could play an important role in phosgene oxime-induced skin injury. • Phosgene oxime could induce low blood pressure and hypoxia leading to mortality. • Data is

Cutaneous exposure to vesicant phosgene oxime: Acute effects on the skin and systemic toxicity

Energy Technology Data Exchange (ETDEWEB)

Tewari-Singh, Neera, E-mail: Neera.tewari-singh@ucdenver.edu [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Goswami, Dinesh G; Kant, Rama [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Croutch, Claire R; Casillas, Robert P [MRIGlobal, Kansas City, MO 64110 (United States); Orlicky, David J [Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Agarwal, Rajesh [Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States)

2017-02-15

Phosgene Oxime (CX), an urticant or nettle agent categorized as a vesicant, is a potential chemical warfare and terrorist weapon. Its exposure can result in widespread and devastating effects including high mortality due to its fast penetration and ability to cause immediate severe cutaneous injury. It is one of the least studied chemical warfare agents with no effective therapy available. Thus, our goal was to examine the acute effects of CX following its cutaneous exposure in SKH-1 hairless mice to help establish a relevant injury model. Results from our study show that topical cutaneous exposure to CX vapor causes blanching of exposed skin with an erythematous ring, necrosis, edema, mild urticaria and erythema within minutes after exposure out to 8 h post-exposure. These clinical skin manifestations were accompanied with increases in skin thickness, apoptotic cell death, mast cell degranulation, myeloperoxidase activity indicating neutrophil infiltration, p53 phosphorylation and accumulation, and an increase in COX-2 and TNFα levels. Topical CX-exposure also resulted in the dilatation of the peripheral vessels with a robust increase in RBCs in vessels of the liver, spleen, kidney, lungs and heart tissues. These events could cause a drop in blood pressure leading to shock, hypoxia and death. Together, this is the first report on effects of CX cutaneous exposure, which could help design further comprehensive studies evaluating the acute and chronic skin injuries from CX topical exposure and elucidate the related mechanism of action to aid in the identification of therapeutic targets and mitigation of injury. - Highlights: • Phosgene oxime cutaneous exposure causes skin blanching, edema and urticaria. • Penetration of phosgene oxime causes dilation of vasculature in internal organs. • Mast cells could play an important role in phosgene oxime-induced skin injury. • Phosgene oxime could induce low blood pressure and hypoxia leading to mortality. • Data is

Immune sensitization to methylene diphenyl diisocyanate (MDI resulting from skin exposure: albumin as a carrier protein connecting skin exposure to subsequent respiratory responses

Directory of Open Access Journals (Sweden)

Redlich Carrie A

2011-03-01

Full Text Available Abstract 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

The biodisposition and hypertrichotic effects of bimatoprost in mouse skin

Science.gov (United States)

Woodward, David F; Tang, Elaine S-H; Attar, Mayssa; Wang, Jenny W

2013-01-01

Studies on bimatoprost were performed with two objectives: (i) to determine whether bimatoprost possesses hair growth-stimulating properties beyond eyelash hypertrichosis and (ii) to investigate the biodisposition of bimatoprost in skin for the first time. Bimatoprost, at the dose used clinically for eyelash growth (0.03%) and given once daily for 14 days, increased pelage hair growth in C57/black 6 mice. This occurred as a much earlier onset of new hair growth in shaved mice and the time taken to achieve complete hair regrowth, according to photographic documentation and visual assessment. Bimatoprost biodisposition in the skin was determined at three concentrations: 0.01%, 0.03% and 0.06%. Dose-dependent Cmax values were obtained (3.41, 6.74, 12.3 μg/g tissue), and cutaneous bimatoprost was well maintained for 24 h following a single dose. Bimatoprost was recovered from the skin only as the intact molecule, with no detectable levels of metabolites. Thus, bimatoprost produces hypertrichosis as the intact molecule. PMID:23278986

Red tattoos, ultraviolet radiation and skin cancer in mice.

Science.gov (United States)

Lerche, Catharina M; Heerfordt, Ida M; Serup, Jørgen; Poulsen, Thomas; Wulf, Hans Christian

2017-11-01

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group (182 vs 186 days and 196 vs 203 days, P=ns). Statistically, the third tumor appeared slightly faster in the red-tattooed group than in the controls (214 vs 224 days, P=.043). For the second and third tumor, the growth rate was faster in the red-tattooed group compared with the control (31 vs 49 days, P=.009 and 30 vs 38 days, P=.036). In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumor onset regarding the third tumor, and faster growth rate of the second and third tumor indicating red ink acts as a cocarcinogen with UVR. The cocarcinogenic effect was weak and may not be clinically relevant. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemopreventive efficacy of betel leaf extract and its constituents on 7,12-dimethylbenz(a)anthracene induced carcinogenesis and their effect on drug detoxification system in mouse skin.

Science.gov (United States)

Azuine, M A; Amonkar, A J; Bhide, S V

1991-04-01

Effects of topically applied betel leaf extract (BLE) and its constituents. beta-carotene, alpha-tocopherol, eugenol and hydroxychavicol on 7,12-dimethylbenz(a)anthracene (DMBA) induced skin tumors were evaluated in two strains of mice. BLE, beta-carotene and alpha-tocopherol, significantly inhibited the tumor formation by 83, 86, 86% in Swiss mice and 92, 94 and 89% in male Swiss bare mice respectively. Hydroxychavicol showed 90% inhibition in Swiss bare mice at 24 weeks of treatment. Eugenol showed minimal protection in both strains of mice. The mean latency period and survivors in BLE, beta-carotene, alpha-tocopherol and hydroxychavicol treated groups were remarkably high as compared to DMBA alone treated group. Intraperitoneal injection of betal leaf constituents showed a significant effect on both glutathione and glutathione S-transferase levels in the Swiss mouse skin.

Biogenic silica fibre promotes carcinogenesis in mouse skin.

Science.gov (United States)

Bhatt, T; Coombs, M; O'Neill, C

1984-10-15

Silica fibres derived from plants are common contaminants of human diet in certain regions of the world where oesophageal cancer reaches extremely high incidences. We show here that one of these types of fibre (derived from Phalaris canariensis L) promotes the occurrence of tumours in the skin of mice initiated with a polycyclic carcinogen. Three experiments are described. In the first, the grain which bears these fibres was added to the diet. This did not result in any abnormality in any part of the gastrointestinal tract, but there was a significant induction of tumours in the skin around the mouth and nose; these were the areas of the body surface which most frequently came into contact with the grain. In the second experiment, the mice were separated from the grain by an intervening wire gauze barrier; a similar number of tumours appeared on initiated mice treated in this way. In this case, contact now occurred most frequently on the dorsal surface, which was rubbed against the gauze barrier, and it was on this surface that the tumours appeared. No tumours appeared if the grain was removed. In the third experiment, pure fibres were isolated from the surface of the grain and boiled in strong nitric acid so as to remove any organic material. When these acid-cleaned fibres were applied to the initiated skin with light pressure, they promoted carcinogenesis in the same way as croton oil. In each experiment the majority of tumours produced were benign neoplasms, together with at least one squamous carcinoma. It seems possible that the size and shape of these fibres are the critical properties determining their promoting activity. Their mean diameter is 15 microns, their modal length close to 200 microns, and they are sharply pointed with a tip diameter of 0.5 micron.

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

International Nuclear Information System (INIS)

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

2013-01-01

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. Highlights: ► Mouse angiogenesis study on reinforced poly(ethylene glycol)-chitosan (RPC) ► Water vapor transmission rate of about 2000 g/m 2 /day is characteristic of RPC. ► RPC suppressed inflammatory cells and accelerated fibroblast proliferation. ► RPC composed of 1000-RP10C90 can be used as a biomaterial for wound dressing

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

Energy Technology Data Exchange (ETDEWEB)

Chen, Szu-Hsien [Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China); Tsao, Ching-Ting [Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China); Epithelial Biology Laboratory/Transgenic Mice Core-Laboratory, Department of Anatomy, Chang Gung University, Taoyuan 33302, Taiwan (China); Chang, Chih-Hao [Department of Orthopedics, National Taiwan University Hospital, Taiwan (China); National Taiwan University College of Medicine, No. 1, Jen-Ai Road, Taipei City 10018, Taiwan (China); Lai, Yi-Ting [Department of Chemical Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China); Wu, Ming-Fung [Animal Medicine Center, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Taipei City 10018, Taiwan (China); Chuang, Ching-Nan [Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China); Chou, Hung-Chia [Department of Chemical Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China); Wang, Chih-Kuang, E-mail: ckwang@kmu.edu.tw [Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan (China); Hsieh, Kuo-Haung, E-mail: khhsieh@ntu.edu.tw [Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei City 10617, Taiwan (China)

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{sup 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. Highlights: ► Mouse angiogenesis study on reinforced poly(ethylene glycol)-chitosan (RPC) ► Water vapor transmission rate of about 2000 g/m{sup 2}/day is characteristic of RPC. ► RPC suppressed inflammatory cells and accelerated fibroblast proliferation. ► RPC composed of 1000-RP10C90 can be used as a biomaterial for wound dressing.

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

Science.gov (United States)

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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

40 CFR 795.232 - Inhalation and dermal pharmacokinetics of commercial hexane.

Science.gov (United States)

2010-07-01

... studies of volatile solvents in hairless mice. I. Description of a skin depot”, In: Journal of Applied... concentration. (C) Dermal studies. The test substance shall be applied and kept on the skin for a minimum of 6... data shall be evaluated by appropriate statistical methods. (3) Reporting results. In addition to the...

Combination chemoprevention with diclofenac, calcipotriol and difluoromethylornithine inhibits development of non-melanoma skin cancer in mice

DEFF Research Database (Denmark)

Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, Jacob

2013-01-01

Background/Aim: With increasing incidence of non-melanoma skin cancer (NMSC), focus on chemoprevention of this disease is growing. The aim of this study was to evaluate topical combination therapies as chemoprevention of UV radiation-induced tumors in a mouse model.......Background/Aim: With increasing incidence of non-melanoma skin cancer (NMSC), focus on chemoprevention of this disease is growing. The aim of this study was to evaluate topical combination therapies as chemoprevention of UV radiation-induced tumors in a mouse model....

Dose-modifying factors for skin ulceration in mouse legs exposed to gamma rays

International Nuclear Information System (INIS)

Masuda, Kouji; Miyoshi, Makoto; Uehara, Satoru; Omagari, Junichi; Withers, H.R.

1996-01-01

To assess the dose-modifying factors for skin ulceration, the hind legs of mice were irradiated using gamma-rays of various doses in single exposures. The skin ulceration began to occur 2 months after irradiation, after early skin reactions such as wet desquamation, had healed completely. No new skin ulceration was observed more than 8 months after irradiation even though the observations were continued until 12 months post-irradiation. The ulceration dose 50 (UD50), a dose required to produce skin ulceration in from 2 to 8 months in 50% of the tested animals, was calculated for each treatment schedule. The preliminary shaving procedure reduced the UD50 dose to 0.85 that of the untreated controls. The ventral aspect of the hind leg was more radioresistant to single-dose irradiation than was to the dorsal aspect. The UD50 for the ventral aspect was 1.29 times that for the dorsal aspect when the skin had been previously shaved, and 1.46 times that for the unshaved control legs. The UD50 was 7 and 14% larger when mice were kept in the dorsal rather than the abdominal position during irradiation, for the preliminarily shaved and unshaved skin, respectively. (author)

X-rays and photocarcinogenesis in hairless mice

DEFF Research Database (Denmark)

Lerche, Catharina M; Philipsen, Peter A; Wulf, Hans Christian

2013-01-01

It is well known that excessive X-ray radiation can cause non-melanoma skin cancers. With the increased incidence of sun-related skin cancer there is a need to investigate the combination of sunlight and X-rays. Immunocompetent C3.Cg/TifBomTac mice (n = 298) were divided into 12 groups. Mice were...

Provocation of skin graft rejection across murine class II differences by non--bone-marrow-derived cells

International Nuclear Information System (INIS)

Stuart, P.M.; Beck-Maier, B.; Melvold, R.W.

1984-01-01

We have evaluated the relative contribution of bone-marrow-derived cells to skin allograft immunogenicity in mice differing only at class II major histocompatibility genes by using bone marrow radiation chimeras as donors. The mouse strains used were C57BL/6Kh (B6) and B6.C-H-2bm12 (bm12), which differ only at at A beta gene of the I region of the mouse H-2 complex. Our results demonstrated that skin from (B6----bm12) chimeras was accepted by bm12 recipients and rejected by B6 mice in a manner indistinguishable from that of normal bm12 skin. Likewise, naive bm12 mice rejected (bm12----B6) chimeric skin and normal B6 skin equally well, and B6 animals accepted both types of skin grafts. Our data argues that the donor cell-type leading to graft rejection across limited I region differences is not of bone marrow origin, and that these cells must--at least under certain circumstances--express class II antigens

Novel Tissue Models of Junctional Epidermolysis Bullosa to Characterize Functional Mechanisms of Sulfur Mustard Injury to Human Skin

National Research Council Canada - National Science Library

Garlick, Joanthan

2003-01-01

In the second year of our research, our laboratory has extensively studied skin pathophysiology in response to SM by adapting in vivo, human skin/nude mouse chimera to further understand mechanisms...

In vivo stepwise multi-photon activation fluorescence imaging of melanin in human skin

Science.gov (United States)

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.

Kaempferol targets RSK2 and MSK1 to suppress ultraviolet radiation-induced skin cancer

Science.gov (United States)

Langfald, Alyssa; Yang, Ge; Zhang, Yi; Yu, Dong Hoon; Kim, Myoung Ok; Lee, Mee-Hyun; Li, Haitao; Bae, Ki Beom; Kim, Hong-Gyum; Ma, Wei-Ya; Bode, Ann M.; Dong, Ziming; Dong, Zigang

2014-01-01

Solar ultraviolet (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the USA. The mitogen-activated protein (MAP) kinase cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAP kinase cascades. In this study, phosphorylation of RSK and MSK1 was up-regulated in human squamous cell carcinoma (SCC) and solar UV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate solar UV-induced phosphorylation of CREB and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of solar UV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in solar UV-induced phosphorylation of cAMP response element-binding protein (CREB), c-Fos and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against solar UV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. PMID:24994661

Kaempferol targets RSK2 and MSK1 to suppress UV radiation-induced skin cancer.

Science.gov (United States)

Yao, Ke; Chen, Hanyong; Liu, Kangdong; Langfald, Alyssa; Yang, Ge; Zhang, Yi; Yu, Dong Hoon; Kim, Myoung Ok; Lee, Mee-Hyun; Li, Haitao; Bae, Ki Beom; Kim, Hong-Gyum; Ma, Wei-Ya; Bode, Ann M; Dong, Ziming; Dong, Zigang

2014-09-01

Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. ©2014 American Association for Cancer Research.

Blue light-induced oxidative stress in live skin.

Science.gov (United States)

Nakashima, Yuya; Ohta, Shigeo; Wolf, Alexander M

2017-07-01

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. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of dermal-epidermal skin equivalents ('composite-skin') of human keratinocytes in a collagen-glycosaminoglycan matrix(Integra artificial skin).

Science.gov (United States)

Kremer, M; Lang, E; Berger, A C

2000-09-01

origin. These experimental results demonstrate the establishment of an effective cell cultivation process which may be suitable for scale-up production of the epidermal component as large-scale composite-skin grafts. When seeded into Integratrade mark and grafted onto the nude mouse a replacement skin with normal functioning dermal-epidermal components was developed. These results encourage the design of a clinical trial to assess the function of this composite graft in man.

Liquid Crystal Gel Reduces Age Spots by Promoting Skin Turnover

OpenAIRE

Mina Musashi; Ariella Coler-Reilly; Teruaki Nagasawa; Yoshiki Kubota; Satomi Kato; Yoko Yamaguchi

2014-01-01

Studies have shown that liquid crystals structurally resembling the intercellular lipids in the stratum corneum can beneficially affect the skin when applied topically by stimulating the skin’s natural regenerative functions and accelerating epidermal turnover. In the present study, the effects of applying low concentrations of a liquid crystal gel of our own creation were evaluated using epidermal thickening in mouse skin as an assay for effective stimulation of epidermal turnover. A liquid ...

EGFR Activation and Ultraviolet Light‐Induced Skin Carcinogenesis

Directory of Open Access Journals (Sweden)

Taghrid B. El-Abaseri

2007-01-01

Full Text Available The epidermal growth factor receptor (EGFR regulates the proliferation of keratinocytes through multiple mechanisms that differ depending on the localization of the cell within the skin. Ultraviolet (UV irradiation, the main etiologic factor in the development of skin cancer, also activates the receptor. In this review, we discuss how the UV-induced activation of EGFR regulates the response of the skin to UV. UV-induced EGFR activation increases keratinocyte proliferation, suppresses apoptosis, and augments and accelerates epidermal hyperplasia in response to UV. Pharmacological inhibition of the UV-induced activation of EGFR in a genetically initiated mouse skin tumorigenesis model suppresses tumorigenesis and the activation of mitogen-activated protein (MAP kinases and phosphatidyl inositol-3-kinase (PI3K/AKT signaling pathways. EGFR has pleiotropic, complex, and cell-type-specific functions in cutaneous keratinocytes; suggesting that the receptor is an appropriate target for the development of molecularly targeted therapies for skin cancer and other pathologies.

The response of mouse skin and lung to fractionated x-rays

International Nuclear Information System (INIS)

Field, S.B.; Hornsey, S.

1975-01-01

The relationship between total dose and number of fractions has been investigated for damage to lung and skin in mice. Single doses and various numbers of fractions have been given and the results are analysed in two ways: (i) by comparing the fractionated treatment with a single dose. With this approach, and assuming that the observed damage to lung and skin is the result of cell killing, it is estimated that the ratio of initial to final slope of the cell survival curve is about 7:1; (ii) by measuring the additional dose required when the number of fractions is doubled. These results are roughly fitted by a single-hit times multitarget survival-curve model, with the ratio of slopes about 3:1. It is concluded from this discrepancy that the two-component model is an inadequate description of the survival curve for the cells of either skin or lung. (author)

The bald and the beautiful: hairlessness in domestic dog breeds

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Harris, Alexander; Dreger, Dayna L.; Davis, Brian W.; Ostrander, Elaine A.

2017-01-01

An extraordinary amount of genomic variation is contained within the chromosomes of domestic dogs, manifesting as dramatic differences in morphology, behaviour and disease susceptibility. Morphology, in particular, has been a topic of enormous interest as biologists struggle to understand the small window of dog domestication from wolves, and the division of dogs into pure breeding, closed populations termed breeds. Many traits related to morphology, including body size, leg length and skull shape, have been under selection as part of the standard descriptions for the nearly 400 breeds recognized worldwide. Just as important, however, are the minor traits that have undergone selection by fanciers and breeders to define dogs of a particular appearance, such as tail length, ear position, back arch and variation in fur (pelage) growth patterns. In this paper, we both review and present new data for traits associated with pelage including fur length, curl, growth, shedding and even the presence or absence of fur. Finally, we report the discovery of a new gene associated with the absence of coat in the American Hairless Terrier breed. This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’. PMID:27994129

Copaiba oil enhances in vitro/in vivo cutaneous permeability and in vivo anti-inflammatory effect of celecoxib.

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Quiñones, Oliesia Gonzalez; Hossy, Bryan Hudson; Padua, Tatiana Almeida; Miguel, Nádia Campos de Oliveira; Rosas, Elaine Cruz; Ramos, Mônica Freiman de Souza; Pierre, Maria Bernadete Riemma

2018-03-29

The aim of this article was to use copaiba oil (C.O) to improve skin permeability and topical anti-inflammatory activity of celecoxib (Cxb). Formulations containing C.O (1-50%) were associated with Cxb (2%). In vitro skin permeability studies were conducted using porcine ear skin. Histological analysis of the hairless mice skin samples after application of formulations was achieved with the routine haematoxylin/eosin technique. The anti-inflammatory activity was assessed using the AA-induced ear oedema mice model. The formulation containing 25% C.O promoted the highest levels of in vitro Cxb permeation through pig ear skin, retention in the stratum corneum (SC) and epidermis/dermis of pig ear skin in vitro (~5-fold) and hairless mice skin in vivo (~2.0-fold), as compared with the control formulation. At 25%, C.O caused SC disorganization and increased cell infiltration and induced angiogenesis without clear signs of skin irritation. The formulation added to 25% C.O as adjuvant inhibited ear oedema and protein extravasation by 77.51 and 89.7%, respectively, and that it was, respectively, 2.0- and 3.4-fold more efficient than the commercial diethylammonium diclofenac cream gel to suppress these inflammatory parameters. 25% C.O is a potential penetration enhancer for lipophilic drugs like Cxb that can improve cutaneous drug penetration and its anti-inflammatory activity. © 2018 Royal Pharmaceutical Society.

Nanodiamonds protect skin from ultraviolet B-induced damage in mice.

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Wu, Meng-Si; Sun, Der-Shan; Lin, Yu-Chung; Cheng, Chia-Liang; Hung, Shih-Che; Chen, Po-Kong; Yang, Jen-Hung; Chang, Hsin-Hou

2015-05-07

Solar ultraviolet (UV) radiation causes various deleterious effects, and UV blockage is recommended for avoiding sunburn. Nanosized titanium dioxide and zinc oxide offer effective protection and enhance cosmetic appearance but entail health concerns regarding their photocatalytic activity, which generates reactive oxygen species. These concerns are absent in nanodiamonds (NDs). Among the UV wavelengths in sunlight, UVB irradiation primarily threatens human health. The efficacy and safety of NDs in UVB protection were evaluated using cell cultures and mouse models. We determined that 2 mg/cm(2) of NDs efficiently reduced over 95% of UVB radiation. Direct UVB exposure caused cell death of cultured keratinocyte, fibroblasts and skin damage in mice. By contrast, ND-shielding significantly protected the aforementioned pathogenic alterations in both cell cultures and mouse models. NDs are feasible and safe materials for preventing UVB-induced skin damage.

Protective effect of (-)-epigallocatechin gallate on ultraviolet b ...

African Journals Online (AJOL)

Purpose: To investigate the protective effect of green tea (-)-epigallocatechin gallate (EGCg) on ultraviolet B (UV-B)-induced skin damages in hairless mice in order to develop a natural sunscreen ... hydrophilic cream has also showed high.

Skin vaccination against cervical cancer associated human papillomavirus with a novel micro-projection array in a mouse model.

Directory of Open Access Journals (Sweden)

Holly J Corbett

Full Text Available 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.

Comparison of the transcriptomes of mouse skin derived precursors (SKPs and SKP-derived fibroblasts (SFBs by RNA-Seq.

Directory of Open Access Journals (Sweden)

Yujie Mao

Full Text Available 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.

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

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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.

Moisture absorption and retention properties, and activity in alleviating skin photodamage of collagen polypeptide from marine fish skin.

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Hou, Hu; Li, Bafang; Zhang, Zhaohui; Xue, Changhu; Yu, Guangli; Wang, Jingfeng; Bao, Yuming; Bu, Lin; Sun, Jiang; Peng, Zhe; Su, Shiwei

2012-12-01

Collagen polypeptides were prepared from cod skin. Moisture absorption and retention properties of collagen polypeptides were determined at different relative humidities. In addition, the protective effects of collagen polypeptide against UV-induced damage to mouse skin were evaluated. Collagen polypeptides had good moisture absorption and retention properties and could alleviate the damage induced by UV radiation. The action mechanisms of collagen polypeptide mainly involved enhancing immunity, reducing the loss of moisture and lipid, promoting anti-oxidative properties, inhibiting the increase of glycosaminoglycans, repairing the endogenous collagen and elastin protein fibres, and maintaining the ratio of type III to type I collagen. Copyright © 2012 Elsevier Ltd. All rights reserved.

Inhibiting Effects of Achyranthes Bidentata Polysaccharide and Lycium Barbarum Polysaccharide on Nonenzyme Glycation in D-galactose Induced Mouse Aging Model

Institute of Scientific and Technical Information of China (English)

HONG-BIN DENG; DA-PENG CUI; JIAN-MING JIANG; YAN-CHUN FENG; NIAN-SHENG CAI; DIAN-DONG LI

2003-01-01

To investigate the inhibiting effects and mechanism of achyranthes bidentata polysaccharide (ABP) and lycium barbarum polysaccharide (LBP) on nonenzyme glycation in D-galactose induced mouse aging model. Methods Serum AGE levels were determined by AGE-ELISA, MTT method was used to determine lymphocyte proliferation, IL-2 activity was determined by a bioassay method. Spontaneous motor activity was used to detect mouse's neuromuscular movement, latency of step-through method was used to examine learning and memory abilities of mouse, colormetric assay was used to determine hydroxyproline concentration in mouse skin, pyrogallol autoxidation method was used to determine superoxide dismutase (SOD) activity of erythrocytes. Results Decreased levels of serum AGE, hydroxyproline concentration in mouse skin and spontaneous motor activity in D-galactose mouse aging model were detected after treated with ABP or LBP, while lymphocyte proliferation and IL-2 activity, learning and memory abilities,SOD activity of erythrocytes, were enhanced. Conclusions ABP and LBP could inhibit nonenzyme glycation in D-galactose induced mouse aging model in vivo and ABP has a better inhibiting effect than LBP.

Anti-skin-aging benefits of exopolymers from Aureobasidium pullulans SM2001.

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Kim, Kyung Hu; Park, Soo Jin; Lee, Ji Eun; Lee, Young Joon; Song, Chang Hyun; Choi, Seong Hun; Ku, Sae Kwang; Kang, Su Jin

2014-01-01

There have been many attempts to search for affordable and effective functional cosmetic ingredients, especially from natural sources. As research into developing a functional cosmetic ingredient, we investigated whether exopolymers from Aureobasidium pullulans SM2001 (E-AP-SM2001) exert antioxidant, antiwrinkle, whitening, and skin moisturizing effects. Antioxidant effects of E-AP-SM2001 were determined by measuring free radical scavenging capacity and superoxide dismutase (SOD)-like activity. Antiwrinkle effects were assessed through the inhibition of hyaluronidase, elastase, collagenase, and matrix metalloproteinase (MMP)-1. Whitening effects were measured by tyrosinase inhibition assay, and by melanin formation test in B16/F10 melanoma cells. Skin moisturizing effects were detected by mouse skin water content test. E-AP-SM2001 showed potent DPPH radical scavenging activity and SOD-like effects. Additionally, hyaluronidase, elastase, collagenase, and MMP-1 activities were significantly inhibited by E-AP-SM2001. We also observed that E-AP-SM2001 effectively reduced melanin production by B16/F10 melanoma cells and mushroom tyrosinase activities. Furthermore, significant increases in skin water content were detected in E-AP-SM2001- treated mouse skin, as compared with vehicle-treated control skin. Notably, a mask pack containing E-AP-SM2001 showed a >twofold more extensive moisturizing effect compared with one containing Saccharomycopsis ferment filtrate. Our results suggest that E-AP-SM2001 has adequate antiaging, antiwrinkle, and whitening benefits and skin moisturizing effect. These effects involve reducing hyaluronidase, elastase, collagenase, and MMP-1 activities, as well as inhibition of melanin production and tyrosinase activities. Therefore, the antioxidant E-AP-SM2001 may serve as a predictable functional ingredient.

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis

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Ng, Qimin; Sanda, Gregory E.; Dey, Amit K.; Teague, Heather L.; Sorokin, Alexander V.; Dagur, Pradeep K.; Silverman, Joanna I.; Harrington, Charlotte L.; Rodante, Justin A.; Rose, Shawn M.; Varghese, Nevin J.; Belur, Agastya D.; Goyal, Aditya; Gelfand, Joel M.; Springer, Danielle A.; Bleck, Christopher K.E.; Thomas, Crystal L.; Yu, Zu-Xi; Winge, Mårten C.G.; Kruth, Howard S.; Marinkovich, M. Peter; Joshi, Aditya A.; Playford, Martin P.; Mehta, Nehal N.

2018-01-01

Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. PMID:29321372

The alpha/beta carboxy-terminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 gamma-like proteins

DEFF Research Database (Denmark)

Wolff, S; Talos, F; Palacios, G

2009-01-01

p63, an ancestral transcription factor of the p53 family, has three C-terminal isoforms whose relative in vivo functions are elusive. The p63 gene is essential for skin and limb development, as vividly shown by two independent global knockout mouse models. Both strains, although constructed diffe...

The hr locus and the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in newborn mice

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Connor, M J [Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States); Puhvel, S M [Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States); Sakamoto, M [Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States); Nanthur, J [Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States)

1994-12-01

In mice, the recessive mutation hairless (hr) controls the cutaneous response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but its influence on TCDD's systemic toxicity is unclear. To clarify this, we compared the effects of lactational TCDD exposure on standardized litters of newborn HRS/J mice homozygous for either hr or + that were fostered by haired dams exposed to 0, 6, 8 or 12 [mu]g TCDD/kg body weight on postnatal day 0. At 12 [mu]g/kg, TCDD was lethal to both haired and hairless pups. At the lower doses (6 and 8 [mu]g/kg) the survival of hr/hr pups was significantly lower than +/+ pups. Affected pups succumbed following a 1 to 2-day period of cachexia and wasting. As has been reported for other mouse strains, TCDD exposure impacted on their neonatal development and lessened the time to eye opening for both haired and hairless pups. However, the hairless animals were affected at lower doses than were the haired. The results of this study document that the hr/hr genotype does influence the systemic toxicity of TCDD in mice. (orig.)

The hr locus and the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in newborn mice

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Connor, M.J. (Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States)); Puhvel, S.M. (Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States)); Sakamoto, M. (Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States)); Nanthur, J. (Div. of Dermatology, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA (United States) Research Service, Veterans Administration West Los Angeles Medical Center, Los Angeles, CA (United States))

1994-12-01

In mice, the recessive mutation hairless (hr) controls the cutaneous response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) but its influence on TCDD's systemic toxicity is unclear. To clarify this, we compared the effects of lactational TCDD exposure on standardized litters of newborn HRS/J mice homozygous for either hr or + that were fostered by haired dams exposed to 0, 6, 8 or 12 [mu]g TCDD/kg body weight on postnatal day 0. At 12 [mu]g/kg, TCDD was lethal to both haired and hairless pups. At the lower doses (6 and 8 [mu]g/kg) the survival of hr/hr pups was significantly lower than +/+ pups. Affected pups succumbed following a 1 to 2-day period of cachexia and wasting. As has been reported for other mouse strains, TCDD exposure impacted on their neonatal development and lessened the time to eye opening for both haired and hairless pups. However, the hairless animals were affected at lower doses than were the haired. The results of this study document that the hr/hr genotype does influence the systemic toxicity of TCDD in mice. (orig.)

An extract of Polygonum multiflorum protects against free radical damage induced by ultraviolet B irradiation of the skin

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I.K. Hwang

Full Text Available Over the last decades, the incidence of ultraviolet B (UVB-related skin problems has been increasing. Damages induced by UVB radiation are related to mutations that occur as a result of direct DNA damage and/or the production of reactive oxygen species. We investigated the anti-oxidant effects of a Polygonum multiflorum thumb extract against skin damage induced by UVB irradiation. Female SKH-1 hairless mice were divided into three groups: control (N = 7, distilled water- (N = 10, and P. multiflorum extract-treated (PM, N = 10 groups. The PM (10 g was extracted with 100 mL distilled water, cryo-dried and 9.8 g was obtained. The animals received a topical application of 500 µL distilled water or PM extract (1, 2, 4, 8, and 16%, w/v, dissolved in distilled water for 30 min after UVB irradiation (wavelength 280-320 nm, 300 mJ/cm²; 3 min of the dorsal kin for 14 days, and skin immunohistochemistry and Cu,Zn-superoxide dismutase (SOD1 activity were determined. SOD1 immunoreactivity, its protein levels and activities in the skin were significantly reduced by 70% in the distilled water-treated group after UVB irradiation compared to control. However, in the PM extract-treated groups, SOD1 immunoreactivity and its protein and activity levels increased in a dose-dependent manner (1-16%, w/v, PM extract compared to the distilled water-treated group. SOD1 protein levels and activities in the groups treated with 8 and 16%, w/v, PM extract recovered to 80-90% of the control group levels after UVB. These results suggest that PM extract strongly inhibits the destruction of SOD1 by UV radiation and probably contains anti-skin photoaging agents.

Retinoic acid modulation of ultraviolet light-induced epidermal ornithine decarboxylase activity

International Nuclear Information System (INIS)

Lowe, N.J.; Breeding, J.

1982-01-01

Irradiation of skin with ultraviolet light of sunburn range (UVB) leads to a large and rapid induction of the polyamine biosynthetic enzyme ornithine decarboxylase in the epidermis. Induction of epidermal ornithine decarboxylase also occurs following application of the tumor promoting agent 12-0-tetradecanoylphorbol-13 acetate and topical retinoic acid is able to block both this ornithine decarboxylase induction and skin tumor promotion. In the studies described below, topical application of retinoic acid to hairless mouse skin leads to a significant inhibition of UVB-induced epidermal ornithine decarboxylase activity. The degree of this inhibition was dependent on the dose, timing, and frequency of the application of retinoic acid. To show significant inhibition of UVB-induced ornithine decarboxylase the retinoic acid had to be applied within 5 hr of UVB irradiation. If retinoic acid treatment was delayed beyond 7 hr following UVB, then no inhibition of UVB-induced ornithine decarboxylase was observed. The quantities of retinoic acid used (1.7 nmol and 3.4 nmol) have been shown effective at inhibiting 12-0-tetradecanoyl phorbol-13 acetate induced ornithine decarboxylase. The results show that these concentrations of topical retinoic acid applied either before or immediately following UVB irradiation reduces the UVB induction of epidermal ornithine decarboxylase. The effect of retinoic acid in these regimens on UVB-induced skin carcinogenesis is currently under study

Norathyriol Suppresses Skin Cancers Induced by Solar Ultraviolet Radiation by Targeting ERK Kinases

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Li, Jixia; Malakhova, Margarita; Mottamal, Madhusoodanan; Reddy, Kanamata; Kurinov, Igor; Carper, Andria; Langfald, Alyssa; Oi, Naomi; Kim, Myoung Ok; Zhu, Feng; Sosa, Carlos P.; Zhou, Keyuan; Bode, Ann M.; Dong, Zigang (Cornell); (Guangdong); (UMM)

2012-06-27

Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity. Mechanistic investigations determined that norathyriol acted as an inhibitor of extracellular signal-regulated kinase (ERK)1/2 activity to attenuate UVB-induced phosphorylation in mitogen-activated protein kinases signaling cascades. We confirmed the direct and specific binding of norathyriol with ERK2 through a cocrystal structural analysis. The xanthone moiety in norathyriol acted as an adenine mimetic to anchor the compound by hydrogen bonds to the hinge region of the protein ATP-binding site on ERK2. Norathyriol inhibited in vitro cell growth in mouse skin epidermal JB6 P+ cells at the level of G{sub 2}-M phase arrest. In mouse skin tumorigenesis assays, norathyriol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis indicated that norathyriol mediates its chemopreventive activity by inhibiting the ERK-dependent activity of transcriptional factors AP-1 and NF-{kappa}B during UV-induced skin carcinogenesis. Taken together, our results identify norathyriol as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.

Touch Receptors Undergo Rapid Remodeling in Healthy Skin

Directory of Open Access Journals (Sweden)

Kara L. Marshall

2016-11-01

Full Text Available Sensory tissues exposed to the environment, such as skin, olfactory epithelia, and taste buds, continuously renew; therefore, peripheral neurons must have mechanisms to maintain appropriate innervation patterns. Although somatosensory neurons regenerate after injury, little is known about how these neurons cope with normal target organ changes. To elucidate neuronal plasticity in healthy skin, we analyzed the structure of Merkel-cell afferents, which are gentle touch receptors, during skin remodeling that accompanies mouse hair-follicle regeneration. The number of Merkel cells is reduced by 90% and axonal arbors are simplified during active hair growth. These structures rebound within just days. Computational modeling predicts that Merkel-cell changes are probabilistic, but myelinated branch stability depends on Merkel-cell inputs. Electrophysiology and behavior demonstrate that tactile responsiveness is less reliable during active growth than in resting skin. These results reveal that somatosensory neurons display structural plasticity at the cost of impairment in the reliability of encoding gentle touch.

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

Science.gov (United States)

Kang, So Min; Han, Sangbum; Oh, Jang-Hee; Lee, Young Mee; Park, Chi-Hyun; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-10-01

Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Tissue-engineered skin preserving the potential of epithelial cells to differentiate into hair after grafting.

Science.gov (United States)

Larouche, Danielle; Cuffley, Kristine; Paquet, Claudie; Germain, Lucie

2011-03-01

The aim of this study was to evaluate whether tissue-engineered skin produced in vitro was able to sustain growth of hair follicles in vitro and after grafting. Different tissues were designed. Dissociated newborn mouse keratinocytes or newborn mouse hair buds (HBs) were added onto dermal constructs consisting of a tissue-engineered cell-derived matrix elaborated from either newborn mouse or adult human fibroblasts cultured with ascorbic acid. After 7-21 days of maturation at the air-liquid interface, no hair was noticed in vitro. Epidermal differentiation was observed in all tissue-engineered skin. However, human fibroblast-derived tissue-engineered dermis (hD) promoted a thicker epidermis than mouse fibroblast-derived tissue-engineered dermis (mD). In association with mD, HBs developed epithelial cyst-like inclusions presenting outer root sheath-like attributes. In contrast, epidermoid cyst-like inclusions lined by a stratified squamous epithelium were present in tissues composed of HBs and hD. After grafting, pilo-sebaceous units formed and hair grew in skin elaborated from HBs cultured 10-26 days submerged in culture medium in association with mD. However, the number of normal hair follicles decreased with longer culture time. This hair-forming capacity after grafting was not observed in tissues composed of hD overlaid with HBs. These results demonstrate that epithelial stem cells can be kept in vitro in a permissive tissue-engineered dermal environment without losing their potential to induce hair growth after grafting.

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

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Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Bunde, Kristi L. [College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Harper, Tod A. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); McQuistan, Tammie J. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Löhr, Christiane V. [Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Bramer, Lisa M. [Applied Statistics and Computational Modeling, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Waters, Katrina M. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Tilton, Susan C. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Krueger, Sharon K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); 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.

Erbium-yttrium-aluminum-garnet laser irradiation ameliorates skin permeation and follicular delivery of antialopecia drugs.

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Lee, Woan-Ruoh; Shen, Shing-Chuan; Aljuffali, Ibrahim A; Li, Yi-Ching; Fang, Jia-You

2014-11-01

Alopecia usually cannot be cured because of the available drug therapy being unsatisfactory. To improve the efficiency of treatment, erbium-yttrium-aluminum-garnet (Er-YAG) laser treatment was conducted to facilitate skin permeation of antialopecia drugs such as minoxidil (MXD), diphencyprone (DPCP), and peptide. In vitro and in vivo percutaneous absorption experiments were carried out by using nude mouse skin and porcine skin as permeation barriers. Fluorescence and confocal microscopies were used to visualize distribution of permeants within the skin. Laser ablation at a depth of 6 and 10 μm enhanced MXD skin accumulation twofold to ninefold depending on the skin barriers selected. DPCP absorption showed less enhancement by laser irradiation as compared with MXD. An ablation depth of 10 μm could increase the peptide flux from zero to 4.99 and 0.33 μg cm(-2) h(-1) for nude mouse skin and porcine skin, respectively. The laser treatment also promoted drug uptake in the hair follicles, with DPCP demonstrating the greatest enhancement (sixfold compared with the control). The imaging of skin examined by microscopies provided evidence of follicular and intercellular delivery assisted by the Er-YAG laser. Besides the ablative effect of removing the stratum corneum, the laser may interact with sebum to break up the barrier function, increasing the skin delivery of antialopecia drugs. The minimally invasive, well-controlled approach of laser-mediated drug permeation offers a potential way to treat alopecia. This study's findings provide the basis for the first report on laser-assisted delivery of antialopecia drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

[Effect of ionizing radiation and other factors on the thermal sensitivity of mouse skin].

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Kurpeshev, O K; Konopliannikov, A G

1987-03-01

A study was made of the effect of various agents on skin injury by hyperthermia in experiments on noninbred albino mice. The effects of heating were assessed by the frequency of skin necrosis development. The results of the study showed that irradiation of the skin (30 Gy) before heating did not influence its thermosensitivity whereas heating 45-180 days after irradiation proved more effective. Ethanol, metronidazole, thyrocalcitonin and actinomycin D decreased skin thermosensitivity, and cyclohexamide, serotonin, hyperglycemia and applying a tourniquet increased it. The DMF value for actinomycin D depended on the temperature of heating. One should distinguish between true modification of tissue thermosensitivity (determined by cellular factors) and indirect modification (associated with change in volumetric circulation rate).

Binding and distribution studies in the SENCAR mouse of compounds demonstrating a route-dependent tumorigenic effect

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Carlson, G.P.; Fossa, A.A.; Morse, M.A.; Weaver, P.M.

1986-01-01

Previous investigators have determined that benzo(a)pyrene [B(a)P] was much more effective in causing skin papillomas if applied topically than when administered orally in the initiation-promotion assay in SENCAR mouse. Conversely, urethane and acrylamide caused a higher percentage of mice to develop papillomas and induced more tumors per mouse when given orally. In an attempt to understand the reason for this discrepancy in route dependency, 3 H-benzo(a)pyrene, 14 C-acrylamide were administered as single doses orally or topically to male SENCAR mice. Distribution in skin, stomach, liver, and lung was determined for time periods up to 48 hr. The binding of these compounds to DNA, RNA, and protein in these tissues was determined 6 and 48 hr after administration. For all three compounds, high concentrations were found in the skin following topical application, but very little material reached this target organ following oral administration. In contrast, the internal organs generally contained more material after oral administration. The binding of label compounds to DNA, RNA, and protein generally reflected the distribution data, thus more compound was bound in the stomach, liver, and lung after oral administration compared to topical application, whereas the opposite was true for the skin. This finding was particularly evident for B(a)P. The results suggest that differences in distribution to the skin and binding to macromolecules following oral or topical administration cannot explain the greater tumorigenicity of urethane and acrylamide after oral administration in the SENCAR mouse

The antiviral effectiveness of butylated hydroxytoluene on herpes cutaneous infections in hairless mice

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Keith, A.D.; Arruda, D.; Snipes, W.; Frost, P.

1982-01-01

Hairless mice, cutaneously infected with herpes simplex virus type 1 (HSV-1), were treated topically with butylated hydroxytoluene (BHT). The effectiveness of BHT in shortening the duration of infections was assayed under three conditions. In the first experiments, mice undergoing primary infections with no prior immunity to HSV-1 were utilized. These animals tended to develop deep lesions that were not typical of recurrent HSV-1 infections in humans. A second set of experiments utilized mice that had recovered from a primary infection and that were immunosuppressed by γ irradiation. Immunosuppression was essential for the full development of lesions upon reinfection. The lesions in these animals remained more localized with less tendency to spread into deep tissues. A third set of experiments utilized animals that were subcutaneously inoculated with human serum γ-globulin 24 hr prior to infection. Lesions on these animals also remained localized and did not penetrate into deep tissues. Under all three conditions, BHT was found to be effective in reducing the clearance time of HSV-1 cutaneous lesions when applied topically to the infected area

Effects of topical application of aqueous solutions of hexoses on epidermal permeability barrier recovery rate after barrier disruption.

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Denda, Mitsuhiro

2011-11-01

Previous studies have suggested that hexose molecules influence the stability of phospholipid bilayers. Therefore, the effects of topical application of all 12 stereoisomers of dextro-hexose on the epidermal barrier recovery rate after barrier disruption were evaluated. Immediately after tape stripping, 0.1 m aqueous solution of each hexose was applied on hairless mouse skin. Among the eight dextro-aldohexoses, topical application of altose, idose, mannose and talose accelerated the barrier recovery, while allose, galactose, glucose and gulose had no effect. Among the four dextro-ketohexoses, psicose, fructose, sorbose and tagatose all accelerated the barrier recovery. As the effects of hexoses on the barrier recovery rate appeared within 1 h, the mechanism is unlikely to be genomic. Instead, these hexoses may influence phase transition of the lipid bilayers of lamellar bodies and cell membrane, a crucial step in epidermal permeability barrier homeostasis. © 2011 John Wiley & Sons A/S.

Fractionation of hairless canary seed (Phalaris canariensis) into starch, protein, and oil.

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Abdel-Aal, El-Sayed M; Hucl, Pierre; Patterson, Carol Ann; Gray, Danielle

2010-06-09

Canary seed is an important specialty crop in Canada. The current market for this true cereal (i.e., belonging to the family Poaceae as wheat) is limited to feed for caged birds. However, canary seed holds a promise for many food and industrial applications based on its composition. Three wet milling procedures based on ethanol (E), water (W), and alkaline (A) extractions used in different order were investigated to determine extraction efficiency and purity of starch, protein, oil, and fiber separated from hairless canary seed, a variety developed for human consumption. Highest extraction efficiencies were obtained when canary seed was defatted with ethanol and then extracted with alkali and water (EAW process). Using this process, approximately 92% pure starch, 75% pure protein, and oil were recovered from canary seed groats. The highest purity of protein, however, was obtained when canary seed was fractionated by the EWA process, that is, defatted and then extracted with water followed by alkali. Fiber component separated prior to alkaline extraction contained high amounts of nonfiber components as indicated by its yield. The EAW extraction process seems to be more promising in canary seed fractionation based on recovery and purity of components.

Percutaneous Absorption and Metabolism of Ketoprofen Isopropyl Ester via Excised Nude Mouse‘s and Monkey’s Skin

Institute of Scientific and Technical Information of China (English)

ZHUQuan-gang; HUJin-hong

2003-01-01

Aim:To study percutaneous absorption and metabolism of ketoprofen isopropyl ester (KPE)via excised nude mouse's and monkey's skin.Methods:Excised skin was prepared by surgical excision and enzyme digestion.Sideby-side diffusion cells were used for in vitro permeation studies.The concentrations of KPE and its metabolite in samples were assayed by HPLC.Results:All KPE penetration through whole thickness skin and stripped skin was metabolized to ketoprofen(KP).the concentration of which in the reciiver solution increased linearly with time.As to the nude mouse skin.the steady-state flux of KP through whole thickness skin was 2.5 times that of KPE through the whloe thickness skin,but the KP and KPE remaining in the whole thickness skin after the finishing of KPE penetration was 22.2 times in compered with the KP remaining in the whole thickness skin after the finshing of KP penetration.The rate of formation of the steady state KP from KPE throught dermis was significantly lower than that of KPE through the whole thickness skin.In he monkey skin,the rate of formation of the steady-state KP from KPE through the whole thickness skin was 0.7 times that from KPE through stripped skin.The KP and KPE remaining in the whole thickness skin after the finishing of KPE penetration was 2.0 time that in the stripped skin after the finishing of KPE penetration.The rate of fornation of the steady-state KP from KPE through dermis was lower than that from KPE through the whole thickness skin and the stripped skin.the KP remaining in dermis after the finsihing of KPE penetration was also significantly lower than the KP remaining in the whole thickness skin and the stripped skin after the finishing of KPE penetration.Conclusion:KP esters are of benefit to imporove the local action of KP.and skin esterase metabolism mainly develops in the epidermis.

Liquid Crystal Gel Reduces Age Spots by Promoting Skin Turnover

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Mina Musashi

2014-07-01

Full Text Available Studies have shown that liquid crystals structurally resembling the intercellular lipids in the stratum corneum can beneficially affect the skin when applied topically by stimulating the skin’s natural regenerative functions and accelerating epidermal turnover. In the present study, the effects of applying low concentrations of a liquid crystal gel of our own creation were evaluated using epidermal thickening in mouse skin as an assay for effective stimulation of epidermal turnover. A liquid crystal gel was also applied topically to human facial skin, and analysis was conducted using before-and-after photographs of age spots, measurements of L* values that reflect degree of skin pigmentation, single-layer samples of the stratum corneum obtained via tape-stripping, and measurements of trans-epidermal water loss that reflect the status of the skin’s barrier function. The results suggested that cost-effective creams containing as low as 5% liquid crystal gel might be effective and safely sold as skin care products targeting age spots and other problems relating to uneven skin pigmentation.

Cell-type-specific roles for COX-2 in UVB-induced skin cancer

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Herschman, Harvey

2014-01-01

In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2 flox/flox mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2 flox/flox;K14Cre + mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2 flox/flox;K14Cre + papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2 flox/flox; LysMCre + myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID:24469308

Topical Treatment with Diclofenac, Calcipotriol (Vitamin-D3 Analog) and Difluoromethylornithine (DFMO) Does Not Prevent Nonmelanoma Skin Cancer in Mice

DEFF Research Database (Denmark)

Pommergaard, H C; Burcharth, J; Rosenberg, J

2013-01-01

Nonmelanoma skin cancer is a common cancer type with increasing incidence. The purpose of this study was to evaluate topical application of diclofenac, calcipotriol, and difluoromethylornithine as chemoprevention in a mouse model of ultraviolet light-induced skin tumors, since these agents have...

Induction of short-term biomarkers of tumor promotion in skin of CD-1 mice by petroleum middle distillates: preliminary observations.

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Skisak, C; DiGiovanni, J; Conti, C J; Slaga, T J; Sharma, S; Sagartz, J W; Walborg, E F

1995-01-01

The induction of sustained epidermal hyperplasia in mouse skin has been shown to be a reliable predictor of tumor promoting activity for chemicals as diverse as phorbol esters, anthralins, n-dodecane and organic peroxides (DiGiovanni, 1992). The results contained herein demonstrate that API 81-07 and API 81-10, petroleum middle distillates that exhibit tumor promoting activity in mouse skin, induce epidermal hyperplasia and ODC activity. Other petroleum middle distillates (odorless light petroleum hydrocarbons, a light vacuum distillate, and a mineral seal oil) were also shown to share these activities. It should be emphasized that the relevance of these observations to human skin remains unresolved; however, the availability of these short-term biomarkers offers the opportunity to address the issue by performing comparative investigations on the effects of petroleum middle distillates on human skin xenografted to athymic (nude) mice. Such studies are being initiated.

Allele-specific deletions in mouse tumors identify Fbxw7 as germline modifier of tumor susceptibility.

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Jesus Perez-Losada

Full Text Available Genome-wide association studies (GWAS have been successful in finding associations between specific genetic variants and cancer susceptibility in human populations. These studies have identified a range of highly statistically significant associations between single nucleotide polymorphisms (SNPs and susceptibility to development of a range of human tumors. However, the effect of each SNP in isolation is very small, and all of the SNPs combined only account for a relatively minor proportion of the total genetic risk (5-10%. There is therefore a major requirement for alternative routes to the discovery of genetic risk factors for cancer. We have previously shown using mouse models that chromosomal regions harboring susceptibility genes identified by linkage analysis frequently exhibit allele-specific genetic alterations in tumors. We demonstrate here that the Fbxw7 gene, a commonly mutated gene in a wide range of mouse and human cancers, shows allele-specific deletions in mouse lymphomas and skin tumors. Lymphomas from three different F1 hybrids show 100% allele-specificity in the patterns of allelic loss. Parental alleles from 129/Sv or Spretus/Gla mice are lost in tumors from F1 hybrids with C57BL/6 animals, due to the presence of a specific non-synonymous coding sequence polymorphism at the N-terminal portion of the gene. A specific genetic test of association between this SNP and lymphoma susceptibility in interspecific backcross mice showed a significant linkage (p = 0.001, but only in animals with a functional p53 gene. These data therefore identify Fbxw7 as a p53-dependent tumor susceptibility gene. Increased p53-dependent tumor susceptibility and allele-specific losses were also seen in a mouse skin model of skin tumor development. We propose that analysis of preferential allelic imbalances in tumors may provide an efficient means of uncovering genetic variants that affect mouse and human tumor susceptibility.

DONG JIE Zhang, LIANG Wang, ZHON

Indian Academy of Sciences (India)

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development, hairless nude skin, and short life (Abitbol et al., 2015; Bryson et al., 2013). On the ... Foxn1 maintains TECs to support T-cell development via mcm2 ... were ligated upstream of the firefly luciferase gene in the plasmid pGL3-Basic.

Development of the mouse dermal adipose layer occurs independently of subcutaneous adipose tissue and is marked by restricted early expression of FABP4.

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Kamila Wojciechowicz

Full Text Available The laboratory mouse is a key animal model for studies of adipose biology, metabolism and disease, yet the developmental changes that occur in tissues and cells that become the adipose layer in mouse skin have received little attention. Moreover, the terminology around this adipose body is often confusing, as frequently no distinction is made between adipose tissue within the skin, and so called subcutaneous fat. Here adipocyte development in mouse dorsal skin was investigated from before birth to the end of the first hair follicle growth cycle. Using Oil Red O staining, immunohistochemistry, quantitative RT-PCR and TUNEL staining we confirmed previous observations of a close spatio-temporal link between hair follicle development and the process of adipogenesis. However, unlike previous studies, we observed that the skin adipose layer was created from cells within the lower dermis. By day 16 of embryonic development (e16 the lower dermis was demarcated from the upper dermal layer, and commitment to adipogenesis in the lower dermis was signalled by expression of FABP4, a marker of adipocyte differentiation. In mature mice the skin adipose layer is separated from underlying subcutaneous adipose tissue by the panniculus carnosus. We observed that the skin adipose tissue did not combine or intermix with subcutaneous adipose tissue at any developmental time point. By transplanting skin isolated from e14.5 mice (prior to the start of adipogenesis, under the kidney capsule of adult mice, we showed that skin adipose tissue develops independently and without influence from subcutaneous depots. This study has reinforced the developmental link between hair follicles and skin adipocyte biology. We argue that because skin adipocytes develop from cells within the dermis and independently from subcutaneous adipose tissue, that it is accurately termed dermal adipose tissue and that, in laboratory mice at least, it represents a separate adipose depot.

Topical W-7 inhibits ultraviolet radiation-induced melanogenesis in Skh:HR2 pigmented hairless mice

International Nuclear Information System (INIS)

Dowdy, J.C.; Anthony, F.A.; Costlow, M.E.

1995-01-01

We studied the effect of N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide (W-7) on ultraviolet radiation (UVR)-induced melanogenesis (tanning) in Skh:HR2 pigmented hairless mice. Topically pretreated mice were exposed to subminimal edematogenic as well as edematogenic UVR doses to establish whether W-7-UVR-induced edema prophylaxis allows increased melanogenesis while preventing edema. Ultraviolet light-irradiated vehicle control animals developed visible trans; however, both W-7-treated groups failed to tan. Topical W-7 before UVR exposure inhibited UVR induction of dopa oxidase activity in melanocytes by 49% (P=0.029) and inhibited UVR-induced deposition of melanin in the epidermis by 88% (P=0.006). Topical W-7 blocked 23% of the UVR but this blockage could not account for the inhibition of dopa oxidase and melanization. We conclude that, in addition to preventing edema, W-7 inhibits UVR-induced melanogenesis, possibly by affecting Ca 2+ -calmodulin and/or protein kinase C-dependent processes. (au) 30 refs

Topical W-7 inhibits ultraviolet radiation-induced melanogenesis in Skh:HR2 pigmented hairless mice

Energy Technology Data Exchange (ETDEWEB)

Dowdy, J.C. [Univ. of Memphis, Div. of Molecular Sciences and Microbiology, Memphis, Tennessee (United States); Anthony, F.A.; Costlow, M.E. [Schering-Plough HealthCare Products, Inc., Advanced Product Research, Memphis, Tennessee (United States)

1995-08-01

We studied the effect of N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide (W-7) on ultraviolet radiation (UVR)-induced melanogenesis (tanning) in Skh:HR2 pigmented hairless mice. Topically pretreated mice were exposed to subminimal edematogenic as well as edematogenic UVR doses to establish whether W-7-UVR-induced edema prophylaxis allows increased melanogenesis while preventing edema. Ultraviolet light-irradiated vehicle control animals developed visible trans; however, both W-7-treated groups failed to tan. Topical W-7 before UVR exposure inhibited UVR induction of dopa oxidase activity in melanocytes by 49% (P=0.029) and inhibited UVR-induced deposition of melanin in the epidermis by 88% (P=0.006). Topical W-7 blocked 23% of the UVR but this blockage could not account for the inhibition of dopa oxidase and melanization. We conclude that, in addition to preventing edema, W-7 inhibits UVR-induced melanogenesis, possibly by affecting Ca{sup 2+}-calmodulin and/or protein kinase C-dependent processes. (au) 30 refs.

COMPARATIVE GENOTOXIC RESPONSES TO ARSENITE IN GUINEA PIG, MOUSE, RAT AND HUMAN LYMPHOCYTES

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Comparative genotoxic responses to arsenite in guinea pig, mouse, rat and human lymphocytes.Inorganic arsenic is a known human carcinogen causing skin, lung, and bladder cancer following chronic exposures. Yet, long-term laboratory animal carcinogenicity studies have ...

The Extract of D. dasycarpus Ameliorates Oxazolone-Induced Skin Damage in Mice by Anti-Inflammatory and Antioxidant Mechanisms.

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Chang, Tsong-Min; Yang, Ting-Ya; Niu, Yu-Lin; Huang, Huey-Chun

2018-06-15

Dictamni dasycarpus is a type of Chinese medicine made from the root bark of D. dasycarpus . It has been reported to show a wide spectrum of biological and pharmacological effects, for example, it has been used widely for the treatment of rheumatism, nettle rash, itching, jaundice, chronic hepatitis and skin diseases. In the current study, D. dasycarpus extract was investigated for its antioxidant and anti-inflammatory effects, as well as its capability to alleviate oxazolone-induced skin damage in mice. The possible anti-inflammatory mechanism of D. dasycarpus extract against oxidative challenge was elucidated by measuring the levels of reactive oxygen species (ROS) production, interleukin-6, Tumor necrosis factor-α, NLRP3 (NACHT, LRR and PYD domains-containing protein 3 (NALP3)) inflammasome and interleukin-1β in HaCaT cells. D. dasycarpus extract did not affect cell viability in basal conditions. The extract significantly reduced oxazolone-induced epidermal swelling compared to untreated animal in the hairless albino mice (ICR mice) model. At the molecular level, Western blot assays indicated that the D. dasycarpus extract attenuated oxazolone-induced activation of apoptosis-associated speck-like protein containing CARD (ASC), procaspase-1, NF-κB and mitogen-activated protein kinase (MAPKs) such as c-Jun N-terminal protein kinase (JNK) and p38. This study demonstrates that D. dasycarpus extract could protect skin cells against oxidative and inflammatory insult by modulating the intracellular levels of ROS, TNF-α, interleukin-1, interleukin-6, NLR family pyrin domain containing 3 (NLRP3) inflammasome generation, antioxidant enzyme activity and cell signaling pathways. D. dasycarpus extract also attenuated the expression of NF-κB in HaCaT keratinocytes and thereby effectively downregulated inflammatory responses in the skin. Furthermore, D. dasycarpus extract alleviated oxazolone-induced damage in mice. Our results suggest the potential application of D

Skin graft influence in human tissue radiated in nude mice regeneration

International Nuclear Information System (INIS)

Miranda, Jurandir Tomaz de

2016-01-01

Over the last few years it has increased the interest in the human skin grafts radio sterilized for application mainly in extensive and deep burns. Because these grafts quickly grip and present antigenic lower potential, compared with other treatments used. The purpose of this study was to evaluate the histoarchitecture of human skin grafts irradiated with doses 25 kGy, 50 kGy and non-irradiated during the repair tissue process in nude mice submitted by skin grafting in the dorsal region. Three groups of animals received irradiated human skin grafts (25 kGy and 50 kGy) and non-irradiated and were euthanized on the 3 rd , 7 th and 21 th day after the surgery. Indeed, routine histologic procedures, tissue samples were stained with hematoxylin and eosin (HE) for quantification of keratinocytes, fibroblasts, immune cells and blood vessels and immunofluorescence (IF) was performed to determine the expression human collagen type I and collagen type I and III mouse. Therefore, quantification of both the cells and the collagen types was performed by image analysis using Image-Pro Plus 6.0 software. Histologic results demonstrated at a dose of 25 kGy that human skin irradiation when grafted influences the increase in the number of cells in wound site over time and it provides better dispersion of these cells. In addition, on the 21 st day, three groups of animals with human skin graft were embedded part of the graft in the healing process. On the other hand, the group not irradiated showed greater incorporation of the graft (43 %), but less production of collagen type III mouse (22 %). Since the groups irradiated skin graft showed lower graft incorporation (6 and 15%), but with greater production of collagen type III mice (35 % and 28 % to 25 kGy and 50 kGy, respectively). In conclusion, this study presented that the group irradiated to 25 kGy and it has a higher cell proliferation and vessel formation, and better remodeling of the healing area. (author)

Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT in mice

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Mondoulet Lucie

2012-11-01

Full Text Available Abstract Background Epicutaneous immunotherapy (EPIT on intact skin with an epicutaneous delivery system has already been used in preclinical and clinical studies. In epicutaneous vaccination and immunotherapy, the stripping of skin before application of the allergen is suggested to facilitate the passage of allergen through immune cells. Objectives The aim of this study was to compare the immunological response induced by EPIT performed on intact and stripped skin in a mouse model of peanut allergy. Methods After oral sensitization with peanut and cholera toxin, BALB/c mice were epicutaneously treated using an epicutaneous delivery system (Viaskin® (DBV Technologies, Paris applied either on intact skin or on stripped skin. Following EPIT, mice received an exclusive oral peanut regimen, aimed at triggering esophageal and jejunal lesions. We assessed eosinophil infiltration by histology, mRNA expression in the esophagus, antibody levels and peripheral T-cell response. Results EPIT on intact skin significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines as well as esophageal eosinophilia (2.7 ± 0.9, compared to Sham 19.9 ± 1.5, p  Conclusions Epicutaneous allergen-specific immunotherapy needs the integrity of superficial layers of the stratum corneum to warranty safety of treatment and to induce a tolerogenic profile of the immune response.

[Effect of topical application of a recombinant adenovirus carrying promyelocytic leukemia gene in a psoriasis-like mouse model].

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Wang, Qiongyu; Zhang, Aijun; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

2013-03-01

To investigate the effects of topical treatment with adenovirus-mediated promyelocytic leukemia gene (PML) gene in a psoriasis-like mouse model. The effect of adenovirus-mediated PML gene on the granular layer of mouse tail scale epidermis and epithelial mitosis were observed on longitudinal histological sections prepared from the tail skin and vaginal epithelium of the mice. Adenovirus-mediated PML gene significantly inhibited mitosis of mouse vaginal epithelial cells and promoted the formation of granular layer in mouse tail scale epidermis. The therapeutic effect of PML gene in the psoriasis-like mouse model may be associated with increased granular cells and suppressed epidemic cell proliferation.

Inhibitory effect of rose hip (Rosa canina L.) on melanogenesis in mouse melanoma cells and on pigmentation in brown guinea pigs.

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Fujii, Takashi; Ikeda, Katsumi; Saito, Morio

2011-01-01

The compounds present in rose hips exerting an inhibitory action against melanogenesis in B16 mouse melanoma cells were investigated by dividing an aqueous extract of rose hips (RE) into four fractions. The 50% ethanol eluate from a DIAION HP-20 column significantly reduced the production of melanin and was mainly composed of procyanidin glycosides. We also found that this 50% ethanol eluate reduced the intracellular tyrosinase activity and also had a direct inhibitory effect on tyrosinase obtained as a protein mixture from the melanoma cell lysate. We also investigated the effect of orally administering RE on skin pigmentation in brown guinea pigs, and found that the pigmentation was inhibited together with the tyrosinase activity in the skin. These data collectively suggest that proanthocyanidins from RE inhibited melanogenesis in mouse melanoma cells and guinea pig skin, and could be useful as a skin-whitening agent when taken orally.

Wound Healing Activity of Extracts and Formulations of Aloe vera, Henna, Adiantum capillus-veneris, and Myrrh on Mouse Dermal Fibroblast Cells.

Science.gov (United States)

Negahdari, Samira; Galehdari, Hamid; Kesmati, Mahnaz; Rezaie, Anahita; Shariati, Gholamreza

2017-01-01

Among the most important factors in wound healing pathways are transforming growth factor beta1 and vascular endothelial growth factor. Fibroblasts are the main cell in all phases wound closure. In this study, the extracts of plant materials such as Adiantum capillus-veneris , Commiphora molmol , Aloe vera , and henna and one mixture of them were used to treatment of normal mouse skin fibroblasts. Cytotoxic effects of each extract and their mixture were assessed on mouse skin fibroblasts cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. We performed migration assays to assess migration properties of mouse skin fibroblasts cells in response to the extracts. Changes in the gene expression of the Tgf β1 and Vegf-A genes were monitored by real-time polymerase chain reaction. A. capillus-veneris , C. molmol and henna extract improved the expression of Tgfβ1 gene. All used extracts upregulated the expression of Vegf-A gene and promoted the migration of mouse fibroblast cells in vitro . The present study demonstrated that the mentioned herbal extracts might be effective in wound healing, through the improvement in the migration of fibroblast cells and regulating the gene expression of Tgfβ1 and Vegf-A genes in fibroblast cells treated with extracts.

Ex vivo multiscale quantitation of skin biomechanics in wild-type and genetically-modified mice using multiphoton microscopy

Science.gov (United States)

Bancelin, Stéphane; Lynch, Barbara; Bonod-Bidaud, Christelle; Ducourthial, Guillaume; Psilodimitrakopoulos, Sotiris; Dokládal, Petr; Allain, Jean-Marc; Schanne-Klein, Marie-Claire; Ruggiero, Florence

2015-12-01

Soft connective tissues such as skin, tendon or cornea are made of about 90% of extracellular matrix proteins, fibrillar collagens being the major components. Decreased or aberrant collagen synthesis generally results in defective tissue mechanical properties as the classic form of Elhers-Danlos syndrome (cEDS). This connective tissue disorder is caused by mutations in collagen V genes and is mainly characterized by skin hyperextensibility. To investigate the relationship between the microstructure of normal and diseased skins and their macroscopic mechanical properties, we imaged and quantified the microstructure of dermis of ex vivo murine skin biopsies during uniaxial mechanical assay using multiphoton microscopy. We used two genetically-modified mouse lines for collagen V: a mouse model for cEDS harboring a Col5a2 deletion (a.k.a. pN allele) and the transgenic K14-COL5A1 mice which overexpress the human COL5A1 gene in skin. We showed that in normal skin, the collagen fibers continuously align with stretch, generating the observed increase in mechanical stress. Moreover, dermis from both transgenic lines exhibited altered collagen reorganization upon traction, which could be linked to microstructural modifications. These findings show that our multiscale approach provides new crucial information on the biomechanics of dermis that can be extended to all collagen-rich soft tissues.

The local lymph node assay and skin sensitization testing.

Science.gov (United States)

Kimber, Ian; Dearman, Rebecca J

2010-01-01

The mouse local lymph node assay (LLNA) is a method for the identification and characterization of skin sensitization hazards. In this context the method can be used both to identify contact allergens, and also determine the relative skin sensitizing potency as a basis for derivation of effective risk assessments.The assay is based on measurement of proliferative responses by draining lymph node cells induced following topical exposure of mice to test chemicals. Such responses are known to be causally and quantitatively associated with the acquisition of skin sensitization and therefore provide a relevant marker for characterization of contact allergic potential.The LLNA has been the subject of exhaustive evaluation and validation exercises and has been assigned Organization for Economic Cooperation and Development (OECD) test guideline 429. Herein we describe the conduct and interpretation of the LLNA.

In Vivo SILAC-Based Proteomics Reveals Phosphoproteome Changes during Mouse Skin Carcinogenesis

NARCIS (Netherlands)

Zanivan, S.; Meves, A.; Behrendt, K.; Schoof, E.M.; Neilson, L.J.; Cox, J.; Tang, H.R.; Kalna, G.; Ree, J.H. van; Deursen, J.M.A. van; Trempus, C.S.; Machesky, L.M.; Linding, R.; Wickstrom, S.A.; Fassler, R.; Mann, M.

2013-01-01

Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic

3T3 fibroblasts induce cloned interleukin 3-dependent mouse mast cells to resemble connective tissue mast cells in granular constituency

International Nuclear Information System (INIS)

Dayton, E.T.; Pharr, P.; Ogawa, M.; Serafin, W.E.; Austen, K.F.; Levi-Schaffer, F.; Stevens, R.L.

1988-01-01

As assessed by ultrastructure, histochemical staining, and T-cell dependency, in vitro-differentiated interleukin 3-dependent mouse mast cells are comparable to the mast cells that reside in the gastrointestinal mucosa but not in the skin or the serosal cavity of the mouse. The authors now demonstrate that when cloned interleukin 3-dependent mast cells are cocultured with mouse skin-derived 3T3 fibroblasts in the presence of WEHI-3 conditioned medium for 28 days, the mast cells acquire the ability to stain with safranin, increase their histamine content ∼ 50-fold and their carboxypeptidase. A content ∼ 100-fold, and augment ∼ their biosynthesis of proteoglycans bearing 35 S-labeled haparin relative to 35 S-labeled chondroitin sulfate glycosaminoglycans. Thus, fibroblasts induce interleukin 3-dependent mouse mast cells to change phenotype from mucosal-like to connective tissue-like, indicating that the biochemical and functional characteristics of this mast cell type are strongly influenced by the connective tissue microenvironment

Stabilization of influenza vaccine enhances protection by microneedle delivery in the mouse skin.

Directory of Open Access Journals (Sweden)

Fu-Shi Quan

2009-09-01

Full Text Available Simple and effective vaccine administration is particularly important for annually recommended influenza vaccination. We hypothesized that vaccine delivery to the skin using a patch containing vaccine-coated microneedles could be an attractive approach to improve influenza vaccination compliance and efficacy.Solid microneedle arrays coated with inactivated influenza vaccine were prepared for simple vaccine delivery to the skin. However, the stability of the influenza vaccine, as measured by hemagglutination activity, was found to be significantly damaged during microneedle coating. The addition of trehalose to the microneedle coating formulation retained hemagglutination activity, indicating stabilization of the coated influenza vaccine. For both intramuscular and microneedle skin immunization, delivery of un-stabilized vaccine yielded weaker protective immune responses including viral neutralizing antibodies, protective efficacies, and recall immune responses to influenza virus. Immunization using un-stabilized vaccine also shifted the pattern of antibody isotypes compared to the stabilized vaccine. Importantly, a single microneedle-based vaccination using stabilized influenza vaccine was found to be superior to intramuscular immunization in controlling virus replication as well as in inducing rapid recall immune responses post challenge.The functional integrity of hemagglutinin is associated with inducing improved protective immunity against influenza. Simple microneedle influenza vaccination in the skin produced superior protection compared to conventional intramuscular immunization. This approach is likely to be applicable to other vaccines too.

Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis

Energy Technology Data Exchange (ETDEWEB)

Chaudhary, Sandeep C.; Singh, Tripti; Kapur, Puneet; Weng, Zhiping; Arumugam, Aadithya; Elmets, Craig A. [Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Avenue South, VH509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd, Suite 2114, Bethesda, MD 20892 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Avenue South, VH509, Birmingham, AL 35294-0019 (United States)

2013-05-01

Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p < 0.05) and volume (p < 0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial–mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways. - Highlights: ► NO-sulindac is a potent chemopreventive agent for UVB-induced skin cancer. ► NO

Controversial role of mast cells in skin cancers.

Science.gov (United States)

Varricchi, Gilda; Galdiero, Maria R; Marone, Giancarlo; Granata, Francescopaolo; Borriello, Francesco; Marone, Gianni

2017-01-01

Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumor initiation and progression. The stromal microenvironment can promote tumor development. Mast cells, widely distributed throughout all tissues, are a stromal component of many solid and haematologic tumors. Mast cells can be found in human and mouse models of skin cancers such as melanoma, basal and squamous cell carcinomas, primary cutaneous lymphomas, haemangiomas and Merkel cell carcinoma. However, human and animal studies addressing potential functions of mast cells and their mediators in skin cancers have provided conflicting results. In several studies, mast cells play a pro-tumorigenic role, whereas in others, they play an anti-tumorigenic role. Other studies have failed to demonstrate a clear role for tumor-associated mast cells. Many unanswered questions need to be addressed before we understand whether tumor-associated mast cells are adversaries, allies or simply innocent bystanders in different types and subtypes of skin cancers. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

Energy Technology Data Exchange (ETDEWEB)

Chang, Yoke-Chen; Wang, James D. [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Svoboda, Kathy K. [Texas A and M University, Baylor College of Dentistry, Center for Craniofacial Research 3302 Gaston Ave, Dallas, Texas 75246 (United States); Casillas, Robert P. [MRIGlobal, 425 Volker Boulevard, Kansas City, MO 64110 (United States); Laskin, Jeffrey D. [UMDNJ-Robert Wood Johnson Medical School, Environmental and Occupational Medicine, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Gordon, Marion K. [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States); Gerecke, Donald R., E-mail: gerecke@eohsi.rutgers.edu [Rutgers University, Pharmacology and Toxicology, 170 Frelinghuysen Rd, Piscataway, NJ 08854 (United States)

2013-04-15

The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. - Highlights: ► We demonstrated ER stress response in the mouse ear vesicant model. ► We described the asymmetrical nature of wound repair in the MEVM. ► We identified the distribution of various ER stress markers in the MEVM.

Establishment of Demodex canis on canine skin engrafted onto scid-beige mice.

Science.gov (United States)

Caswell, J L; Yager, J A; Barta, J R; Parker, W

1996-12-01

A small animal model of canine demodicosis is described. Normal canine skin was engrafted onto scid (severe combined immunodeficient)-beige mice, which lack functional B and T lymphocytes and have reduced natural killer cell activity. The xenografts were later infected with Demodex canis collected from a dog with demodicosis. At 30-112 days following infection, mites were seen histologically in the canine hair follicles of the engrafted skin. Demodex canis adults, nymphs, larvae, and eggs were present in samples macerated in sodium hydroxide. Mite infestations could not be demonstrated in the mouse skin, nor were mites passed from the infected graft to uninfected skin grafts on in-contact mice. This model may be utilized to assess the efficacy of miticidal treatments, to evaluate the importance of specific components of the immune response, and to study the biology of D. canis.

Therapeutic levels of erythropoietin (EPO) achieved after gene electrotransfer to skin in mice

DEFF Research Database (Denmark)

Gothelf, A; Hojman, P; Gehl, Julie

2010-01-01

Gene electrotransfer refers to gene transfection by electroporation and is an effective non-viral method for delivering naked DNA into cells and tissues. This study presents data from gene electrotransfer with erythropoietin (EPO) to mouse skin. Nine-week-old female NMRI mice received one, two...

Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters.

Science.gov (United States)

Fujiki, H; Suganuma, M; Yoshizawa, S; Kanazawa, H; Sugimura, T; Manam, S; Kahn, S M; Jiang, W; Hoshina, S; Weinstein, I B

1989-01-01

Three okadaic acid class tumor promoters, okadaic acid, dinophysistoxin-1, and calyculin A, have potent tumor-promoting activity in two-stage carcinogenesis experiments on mouse skin. DNA isolated from tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) and each of these tumor promoters revealed the same mutation at the second nucleotide of codon 61 (CAA----CTA) in the c-Ha-ras gene, determined by the polymerase chain reaction procedure and DNA sequencing. Three potent 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, TPA, teleocidin, and aplysiatoxin, showed the same effects. These results provide strong evidence that this mutation in the c-Ha-ras gene is due to a direct effect of DMBA rather than a selective effect of specific tumor promoters.

Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.

Science.gov (United States)

Arno, Anna I; Amini-Nik, Saeid; Blit, Patrick H; Al-Shehab, Mohammed; Belo, Cassandra; Herer, Elaine; Tien, Col Homer; Jeschke, Marc G

2014-02-24

The prevalence of nonhealing wounds is predicted to increase due to the growing aging population. Despite the use of novel skin substitutes and wound dressings, poorly vascularized wound niches impair wound repair. Mesenchymal stem cells (MSCs) have been reported to provide paracrine signals to promote wound healing, but the effect of human Wharton's jelly-derived MSCs (WJ-MSCs) has not yet been described in human normal skin. Human WJ-MSCs and normal skin fibroblasts were isolated from donated umbilical cords and normal adult human skin. Fibroblasts were treated with WJ-MSC-conditioned medium (WJ-MSC-CM) or nonconditioned medium. Expression of genes involved in re-epithelialization (transforming growth factor-β2), neovascularization (hypoxia-inducible factor-1α) and fibroproliferation (plasminogen activator inhibitor-1) was upregulated in WJ-MSC-CM-treated fibroblasts (P≤0.05). WJ-MSC-CM enhanced normal skin fibroblast proliferation (P≤0.001) and migration (P≤0.05), and promoted wound healing in an excisional full-thickness skin murine model. Under our experimental conditions, WJ-MSCs enhanced skin wound healing in an in vivo mouse model.

Identification of genes important for cutaneous function revealed by a large scale reverse genetic screen in the mouse.

Directory of Open Access Journals (Sweden)

Tia DiTommaso

2014-10-01

Full Text Available The skin is a highly regenerative organ which plays critical roles in protecting the body and sensing its environment. Consequently, morbidity and mortality associated with skin defects represent a significant health issue. To identify genes important in skin development and homeostasis, we have applied a high throughput, multi-parameter phenotype screen to the conditional targeted mutant mice generated by the Wellcome Trust Sanger Institute's Mouse Genetics Project (Sanger-MGP. A total of 562 different mouse lines were subjected to a variety of tests assessing cutaneous expression, macroscopic clinical disease, histological change, hair follicle cycling, and aberrant marker expression. Cutaneous lesions were associated with mutations in 23 different genes. Many of these were not previously associated with skin disease in the organ (Mysm1, Vangl1, Trpc4ap, Nom1, Sparc, Farp2, and Prkab1, while others were ascribed new cutaneous functions on the basis of the screening approach (Krt76, Lrig1, Myo5a, Nsun2, and Nf1. The integration of these skin specific screening protocols into the Sanger-MGP primary phenotyping pipelines marks the largest reported reverse genetic screen undertaken in any organ and defines approaches to maximise the productivity of future projects of this nature, while flagging genes for further characterisation.

Topical isoflavones provide effective photoprotection to skin.

Science.gov (United States)

Lin, Jing-Yi; Tournas, Joshua A; Burch, James A; Monteiro-Riviere, Nancy A; Zielinski, Jan

2008-04-01

Isoflavones, one main group of phytoestrogens, have antioxidative and photoprotective effects in cellular and mouse studies. The aim of this study is to obtain a more comprehensive understanding of the isoflavone-mediated photoprotection with the pig skin model, a more human-resembling model. The pig skin was treated with five well-known isoflavone compounds (genistein, equol, daidzein, biochanin A, and formononetin) and one antioxidant combination solution of 15% vitamin C and 1% vitamin E and 0.5% ferulic acid (CEF) daily for 4 days. Skin was irradiated with solar-simulated UV irradiation, 1 to 5 minimal erythema dose (MED) at 1-MED intervals. Evaluation was carried out 24 h later by colorimeter-measured erythema and sunburn cell numbers. Topical application of 0.5% solutions of three individual phytoestrogens - genistein, daidzein, biochanin A - are better than similar solutions of equol or formononetin in protecting pig skin from solar-simulated ultraviolet (SSUV)-induced photodamage, as measured by sunburn cell formation and/or erythema. However, the protection was less than that provided by a topical combination antioxidant standard containing 15% L-ascorbic acid, 1%alpha-tocopherol, and 0.5% ferulic acid. Isoflavones provide effective photoprotection and are good candidate ingredients for protection against ultraviolet (UV) photodamage.

Evaluation of the contribution of chronic skin irritation and selected compositional parameters to the tumorigenicity of petroleum middle distillates in mouse skin.

Science.gov (United States)

Freeman, J J; Federici, T M; McKee, R H

1993-07-28

Two-year skin carcinogenicity studies were conducted in C3H mice to assess the effects of irritation and selected compositional parameters on the carcinogenic potential of four petroleum liquids. Three samples (lightly refined paraffinic oil, LRPO; lightly hydrodesulfurized specialty oil, LHSO; jet fuel, JF) can be generically classified as middle distillates, i.e. distillation occurs between 350 and 700 degrees F (175-370 degrees C). The fourth sample was a Steam Cracked Gas Oil (SCGO) that distilled within the same range. In studies that assess the effects of irritation on tumorigenicity, LRPO was tested undiluted or was diluted to 50% and 25% in either mineral oil (which eliminated irritation of the skin) or toluene (which did not). Undiluted LRPO elicited tumors in 8% of the mice. Both dilution procedures eliminated tumorigenic potential. Thus, it was possible to maintain a visible level of skin irritation equivalent to that elicited by undiluted LRPO without inducing tumors. SCGO elicited a chronic irritant state grossly equivalent to LRPO but was not tumorigenic. Jet Fuel A (JF) was tested undiluted using both a standard skin painting protocol and an intermittent dosing schedule in which treatment was suspended periodically to allow skin irritation to resolve. The standard treatment protocol of JF resulted in both marked skin irritation and tumors in 44% of the mice. However, using the intermittent schedule, the tumor yield was reduced to 2%. Collectively these data demonstrate that tumor formation is not a necessary sequelae to chronic skin irritation. Conversely, prevention of a marked chronic irritant state was accompanied by decreased tumor yield. These data suggest that the chronic irritant state may be a necessary but not sufficient condition for tumor formation. In studies to assess the effects of compositional parameters, a lightly hydrodesulfurized specialty oil (LHSO) similar to LRPO but refined to have negligible levels of sulfur compounds (3 ppm

Effects of low or high doses of short wavelength ultraviolet light (UVB) on Langerhans cells and skin allograft survival

International Nuclear Information System (INIS)

Odling, K.A.; Halliday, G.M.; Muller, H.K.

1987-01-01

Donor C57BL mouse shaved dorsal trunk or tail skin was exposed to high (200 mJ/cm 2 ) or low (40 mJ/cm 2 ) doses of short wavelength ultraviolet light (UVB) before grafting on to the thorax of BALB/c mouse recipients of the same sex. Skin grafted 1-14 days following a single high dose of UVB irradiation was ultrastructurally depleted of LC and survived significantly longer than unirradiated skin before being rejected. After a 21-day interval between exposure and grafting when LC were again present in the epidermis there was no significant difference between treated and control graft survival. Exposure to low dose UVB irradiation only significantly increased graft survival for skin transplanted 1-3 days after irradiation; skin grafted 4 days following irradiation survived for a similar period to unirradiated control skin grafts. Electronmicroscopy showed that the low UVB dose did not deplete LC from the epidermis. We conclude that after low dose UVB treatment the class II MHC antigens on the LC Plasma membrane were lost temporarily, thus prolonging graft survival, but when the plasma membrane antigens were re-expressed graft survival returned to normal. In contrast, high-dose UVB irradiation prolonged graft survival by depleting LC from the epidermis, with graft survival only returning to control values as LC repopulated the epidermis

The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men.

Energy Technology Data Exchange (ETDEWEB)

Lehman, J M [University of Alabama, Birmingham; Michaud III, Edward J [ORNL; Schoeb, T [University of Alabama, Birmingham; Aydin Son, Yesim [University of Tennessee, Knoxville (UTK); Miller, M [University of Alabama, Birmingham; Yoder, Bradley [University of Alabama, Birmingham

2008-08-01

The Oak Ridge Polycystic Kidney (ORPK) mouse was described nearly 14 years ago as a model for human recessive polycystic kidney disease. The ORPK mouse arose through integration of a transgene into an intron of the Ift88 gene resulting in a hypomorphic allele (Ift88Tg737Rpw). The Ift88Tg737Rpw mutation impairs intraflagellar transport (IFT), a process required for assembly of motile and immotile cilia. Historically, the primary immotile cilium was thought to have minimal importance for human health; however, a rapidly expanding number of human disorders have now been attributed to ciliary defects. Importantly, many of these phenotypes are present and can be analyzed using the ORPK mouse. In this review, we highlight the research conducted using the OPRK mouse and the phenotypes shared with human cilia disorders. Furthermore, we describe an additional follicular dysplasia phenotype in the ORPK mouse, which alongside the ectodermal dysplasias seen in human Ellis-van Creveld and Sensenbrenner's syndromes, suggests an unappreciated role for primary cilia in the skin and hair follicle.

Treating cutaneous squamous cell carcinoma using 5-aminolevulinic acid polylactic-co-glycolic acid nanoparticle-mediated photodynamic therapy in a mouse model

Directory of Open Access Journals (Sweden)

Wang X

2015-01-01

Full Text Available Xiaojie Wang,1,2,* Lei Shi,2,* Qingfeng Tu,2 Hongwei Wang,3 Haiyan Zhang,2 Peiru Wang,2 Linglin Zhang,2 Zheng Huang,4 Feng Zhao,5 Hansen Luan,5 Xiuli Wang2 1Shanghai Skin Diseases Clinical College of Anhui Medical University, 2Shanghai Skin Disease Hospital, 3Huadong Hospital, Fudan University, Shanghai, 4MOE Key Laboratory of OptoElectronic Science and Technology for Medicine, Fujian Normal University, Fuzhou, 5National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, People’s Republic of China *These authors contributed equally to this study Background: Squamous cell carcinoma (SCC is a common skin cancer, and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP-assisted 5-aminolevulinic acid (ALA delivery for topical photodynamic therapy (PDT of cutaneous SCC.Materials and methods: Ultraviolet-induced cutaneous SCCs were established in hairless mice. ALA-loaded polylactic-co-glycolic acid (PLGA NPs were prepared and characterized. The kinetics of ALA PLGA NP-induced protoporphyrin IX fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined.Results: PLGA NPs enhanced protoporphyrin IX production in SCC. ALA PLGA NP-mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC.Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC. Keywords: 5-aminolevulinic acid (ALA, polylactic-co-glycolic acid (PLGA, nanoparticles (NPs, cutaneous squamous cell carcinoma (SCC, photodynamic therapy (PDT, microneedling

A 90-day toxicity study of the effects of petroleum middle distillates on the skin of C3H mice.

Science.gov (United States)

Freeman, J J; McKee, R H; Phillips, R D; Plutnick, R T; Scala, R A; Ackerman, L J

1990-01-01

Petroleum middle distillates (PMDs) elicit skin tumors in mouse epidermal carcinogenesis studies. The response is characterized by a long latency with only a small percentage of animals developing tumors. Although the carcinogenic activity of certain other petroleum hydrocarbons largely depends upon the presence of polycyclic aromatic hydrocarbons (PAHs), many PMDs contain relatively low concentrations of PAHs. PMDs are also irritating to mouse skin, and chronic irritation may be involved in the development of skin tumors. This study was conducted to investigate the patterns of cutaneous irritation elicited by topical application of PMDs having compositional differences. The three PMDs selected for study were a steam cracked gas oil (SCGO), a lightly refined paraffinic oil (LRPO), and a jet fuel (JF). Male C3H/HeNCr1BR mice (25/group) were treated topically (37.5 microliters 2x/week for 13 weeks) with 10%, 50% or 100% (undiluted) concentrations of each PMD. Catalytically cracked clarified oil (CCCO, 10%), a potent carcinogen to mouse skin, was also tested. The vehicle was a noncarcinogenic mineral oil with a viscosity of 90 SUS. Cutaneous changes were evaluated by gross observations and light microscopy. Cutaneous irritation was the only significant toxic response in this study. Neither the vehicle nor any of the 10% PMD concentrations produced significant cutaneous irritation. The 10% CCCO and 50% PMD treatments all elicited slight to moderate proliferative and inflammatory changes in mouse skin. Ulcers were also observed microscopically in mice treated with 10% CCCO and 50% SCGO. The 100% SCGO treatment produced evidence of necrosis on Days 1-7 but not later in the study despite continued treatment. In contrast, the irritating effects of 100% LRPO were not evident until 2-3 weeks of study, and at study completion were characterized by moderately severe inflammatory and proliferative changes. The effects of 100% JF were qualitatively similar to 100% LRPO but less

Preventive effect of Dioscorea japonica on squamous cell carcinoma of mouse skin involving down-regulation of prostaglandin E2 synthetic pathway.

Science.gov (United States)

Tsukayama, Izumi; Toda, Keisuke; Takeda, Yasunori; Mega, Takuto; Tanaka, Mitsuki; Kawakami, Yuki; Takahashi, Yoshitaka; Kimoto, Masumi; Yamamoto, Kei; Miki, Yoshimi; Murakami, Makoto; Suzuki-Yamamoto, Toshiko

2018-03-01

Hyperproduced prostaglandin E 2 by cyclooxygenase-2 and microsomal prostaglandin E synthase-1 evokes several pathophysiological responses such as inflammation and carcinogenesis. Our recent study demonstrated that Dioscorea japonica extract suppressed the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and induced apoptosis in lung carcinoma A549 cells. In the present study, we investigated the effects of Dioscorea japonica on squamous cell carcinoma of mouse skin. Dioscorea japonica feeding and Dioscorea japonica extract topical application suppressed the expression of cyclooxygenase-2, microsomal prostaglandin E synthase-1, interleukin-1β and interleukin-6 and inhibited tumor formation, hyperplasia and inflammatory cell infiltration. Immunohistochemical analyses showed the immunoreactivities of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in tumor keratinocytes and stronger immunoreactivities of cyclooxygenase-2 and hematopoietic prostaglandin D synthase in epidermal dendritic cells (Langerhans cells). Treatment with Dioscorea japonica decreased the immunoreactivity of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. These results indicate that Dioscorea japonica may have inhibitory effects on inflammation and carcinogenesis via suppression of the prostaglandin E 2 synthetic pathway.

Quantitative relationship between the local lymph node assay and human skin sensitization assays.

Science.gov (United States)

Schneider, K; Akkan, Z

2004-06-01

The local lymph node assay (LLNA) is a new test method which allows for the quantitative assessment of sensitizing potency in the mouse. Here, we investigate the quantitative correlation between results from the LLNA and two human sensitization tests--specifically, human repeat insult patch tests (HRIPTs) and human maximization tests (HMTs). Data for 57 substances were evaluated, of which 46 showed skin sensitizing properties in human tests, whereas 11 yielded negative results in humans. For better comparability data from mouse and human tests were transformed to applied doses per skin area, which ranged over four orders of magnitude for the substances considered. Regression analysis for the 46 human sensitizing substances revealed a significant positive correlation between the LLNA and human tests. The correlation was better between LLNA and HRIPT data (n=23; r=0.77) than between LLNA and HMT data (n=38; r=0.65). The observed scattering of data points is related to various uncertainties, in part associated with insufficiencies of data from older HMT studies. Predominantly negative results in the LLNA for another 11 substances which showed no skin sensitizing activity in human maximization tests further corroborate the correspondence between LLNA and human tests. Based on this analysis, the LLNA can be considered a reliable basis for relative potency assessments for skin sensitizers. Proposals are made for the regulatory exploitation of the LLNA: four potency groups can be established, and assignment of substances to these groups according to the outcome of the LLNA can be used to characterize skin sensitizing potency in substance-specific assessments. Moreover, based on these potency groups, a more adequate consideration of sensitizing substances in preparations becomes possible. It is proposed to replace the current single concentration limit for skin sensitizers in preparations, which leads to an all or nothing classification of a preparation as sensitizing to

Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin.

Science.gov (United States)

Qiao, W; Li, A G; Owens, P; Xu, X; Wang, X-J; Deng, C-X

2006-01-12

Smad4 is the common mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in skin development and epidermal tumorigenesis, we disrupted this gene in skin using the Cre-loxP approach. We showed that absence of Smad4 blocked hair follicle differentiation and cycling, leading to a progressive hair loss of mutant (MT) mice. MT hair follicles exhibited diminished expression of Lef1, and increased proliferative cells in the outer root sheath. Additionally, the skin of MT mice exhibited increased proliferation of basal keratinocytes and epidermal hyperplasia. Furthermore, we provide evidence that the absence of Smad4 resulted in a block of both TGFbeta and bone morphogenetic protein (BMP) signaling pathways, including p21, a well-known cyclin-dependent kinase inhibitor. Consequently, all MT mice developed spontaneous malignant skin tumors from 3 months to 13 months of age. The majority of tumors are malignant squamous cell carcinomas. A most notable finding is that tumorigenesis is accompanied by inactivation of phosphatase and tensin homolog deleted on chromosome 10 (Pten), activation of AKT, fast proliferation and nuclear accumulation of cyclin D1. These observations revealed the essential functions of Smad4-mediated signals in repressing skin tumor formation through the TGFbeta/BMP pathway, which interacts with the Pten signaling pathway.

Radioprotection of normal tissues of the mouse by hypoxic breathing

International Nuclear Information System (INIS)

Stevens, G.N.; Joiner, B.; Denekamp, J.

1989-01-01

Hypoxic breathing during irradiation has been advocated as a therapeutic modality, to increase the efficacy of radiotherapy. In this form of treatment, the total and daily X-ray dose is increased by a factor of 1.25, on the assumption that all normal tissues in the beam will be protected to a similar extent by breathing gas containing a reduced oxygen concentration (usually 10%). To test this concept, we have determined the effect of varying the inspired oxygen tension on the radiosensitivity of 3 normal tissues in the mouse (kidney, jejunum and skin), and have compared these results with data from the literature for mouse lung. Reduction of the inspired oxygen tension from 21% (air) to 7-8% led to much greater radioprotection of skin (protection factor 1.37) than of lung (1.09). Protection factors for jejunum and kidney were 1.16 and 1.36 respectively. The results show that the extent of radioprotection afforded by hypoxic breathing is tissue dependent, and that great care must be taken clinically in choosing the increased radiation dose to be used in conjunction with hypoxic breathing

Tissue expansion for correction of baldness in aplasia cutis congenita

NARCIS (Netherlands)

Beekmans, S.J.A.; Don Griot, J.P.W.; Niessen, F.B.; Mulder, J.W.

2009-01-01

Aplasia cutis is a congenital absence of the skin, usually presenting on the scalp. In 20% of all cases, part of the skull is also absent. A residual area of baldness may still be present some years after surgical or conservative treatment. It is possible to excise the scarred hairless region and

Caffeine ameliorates radiation-induced skin reactions in mice but does not influence tumour radiation response

Energy Technology Data Exchange (ETDEWEB)

Hebbar, S.A.; Mitra, A.K.; George, K.C.; Verma, N.C. [Radiation Biology Division, Bhabha Atomic Research Centre, Trombay, Mumbai (India)]. E-mail: ncverma@apsara.barc.ernet.in

2002-03-01

Intramuscular administration of caffeine at a dose of 80 mg kg{sup -1} body weight to the gastrocnemius muscles of Swiss mice 5 min prior to local irradiation (35 Gy) of the leg delayed the progression of radiation-induced skin reactions in such animals. While 90% epilation with reddening of the skin was noted in animals treated with radiation alone, animals pretreated with caffeine suffered only partial hair loss with slight reddening of the skin on the 16th and 20th days post-irradiation. Beyond the 28th day, damage scores in irradiated feet for both the groups were similar (score 3) and remained unchanged until the 32nd day and then decreased and disappeared completely in both treatment groups by the 40th day after irradiation. In addition, the effect of caffeine on the radiation response of a mouse fibrosarcoma was investigated. Results showed that intratumoral administration of caffeine at a dose of 80 mg kg{sup -1} body weight 5 min prior to local exposure of tumours to 10 Gy of {sup 60}Co {gamma}-rays did not influence the response of tumours to radiation. The present study thus showed that although caffeine ameliorated radiation-induced skin reactions in the mouse leg, it did not affect the tumour radiation response, indicating its potential application in cancer radiotherapy. (author)