The deceptive nature of UVA tanning versus the modest protective effects of UVB tanning on human skin.

PubMed

Miyamura, Yoshinori; Coelho, Sergio G; Schlenz, Kathrin; Batzer, Jan; Smuda, Christoph; Choi, Wonseon; Brenner, Michaela; Passeron, Thierry; Zhang, Guofeng; Kolbe, Ludger; Wolber, Rainer; Hearing, Vincent J

2011-02-01

The relationship between human skin pigmentation and protection from ultraviolet (UV) radiation is an important element underlying differences in skin carcinogenesis rates. The association between UV damage and the risk of skin cancer is clear, yet a strategic balance in exposure to UV needs to be met. Dark skin is protected from UV-induced DNA damage significantly more than light skin owing to the constitutively higher pigmentation, but an as yet unresolved and important question is what photoprotective benefit, if any, is afforded by facultative pigmentation (i.e. a tan induced by UV exposure). To address that and to compare the effects of various wavelengths of UV, we repetitively exposed human skin to suberythemal doses of UVA and/or UVB over 2 weeks after which a challenge dose of UVA and UVB was given. Although visual skin pigmentation (tanning) elicited by different UV exposure protocols was similar, the melanin content and UV-protective effects against DNA damage in UVB-tanned skin (but not in UVA-tanned skin) were significantly higher. UVA-induced tans seem to result from the photooxidation of existing melanin and its precursors with some redistribution of pigment granules, while UVB stimulates melanocytes to up-regulate melanin synthesis and increases pigmentation coverage, effects that are synergistically stimulated in UVA and UVB-exposed skin. Thus, UVA tanning contributes essentially no photoprotection, although all types of UV-induced tanning result in DNA and cellular damage, which can eventually lead to photocarcinogenesis. 2010 John Wiley & Sons A/S. This article is a US Government work and is in the public domain in the USA.

An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin.

PubMed

Kumar, Rahul; Deep, Gagan; Agarwal, Rajesh

2015-06-01

Skin cancer incidences are rising worldwide, and one of the major causative factors is excessive exposure to solar ultraviolet radiation (UVR). Annually, ~5 million skin cancer patients are treated in United States, mostly with nonmelanoma skin cancer (NMSC), which is also frequent in other Western countries. As sunscreens do not provide adequate protection against deleterious effects of UVR, additional and alternative chemoprevention strategies are urgently needed to reduce skin cancer burden. Over the last couple of decades, extensive research has been conducted to understand the molecular basis of skin carcinogenesis, and to identifying novel agents which could be useful in the chemoprevention of skin cancer. In this regard, several natural non-toxic compounds have shown promising efficacy in preventing skin carcinogenesis at initiation, promotion and progression stages, and are considered important in better management of skin cancer. Consistent with this, we and others have studied and established the notable efficacy of natural flavonolignan silibinin against UVB-induced skin carcinogenesis. Extensive pre-clinical animal and cell culture studies report strong anti-inflammatory, anti-oxidant, DNA damage repair, immune-modulatory and anti-proliferative properties of silibinin. Molecular studies have identified that silibinin targets pleotropic signaling pathways including mitogenic, cell cycle, apoptosis, autophagy, p53, NF-κB, etc. Overall, the skin cancer chemopreventive potential of silibinin is well supported by comprehensive mechanistic studies, suggesting its greater use against UV-induced cellular damages and photocarcinogenesis.

An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin

PubMed Central

Kumar, Rahul; Deep, Gagan; Agarwal, Rajesh

2015-01-01

Skin cancer incidences are rising worldwide, and one of the major causative factors is excessive exposure to solar ultraviolet radiation (UVR). Annually, ~5 million skin cancer patients are treated in United States, mostly with nonmelanoma skin cancer (NMSC), which is also frequent in other Western countries. As sunscreens do not provide adequate protection against deleterious effects of UVR, additional and alternative chemoprevention strategies are urgently needed to reduce skin cancer burden. Over the last couple of decades, extensive research has been conducted to understand the molecular basis of skin carcinogenesis, and to identifying novel agents which could be useful in the chemoprevention of skin cancer. In this regard, several natural non-toxic compounds have shown promising efficacy in preventing skin carcinogenesis at initiation, promotion and progression stages, and are considered important in better management of skin cancer. Consistent with this, we and others have studied and established the notable efficacy of natural flavonolignan silibinin against UVB-induced skin carcinogenesis. Extensive pre-clinical animal and cell culture studies report strong anti-inflammatory, anti-oxidant, DNA damage repair, immune-modulatory and anti-proliferative properties of silibinin. Molecular studies have identified that silibinin targets pleotropic signaling pathways including mitogenic, cell cycle, apoptosis, autophagy, p53, NF-κB, etc. Overall, the skin cancer chemopreventive potential of silibinin is well supported by comprehensive mechanistic studies, suggesting its greater use against UV-induced cellular damages and photocarcinogenesis. PMID:26097804

Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun Yang; Kojima, Chikara; Chignell, Colin

2011-09-15

Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100 nM, 30 weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100 nM) did not induce ODD during the 30 weeks required for malignant transformation. Although acute UV-treatment (UVA, 25 J/cm{supmore » 2}) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (> 50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. - Highlights: > Arsenic transformation adapted to UV-induced apoptosis. > Arsenic transformation diminished oxidant response. > Arsenic transformation enhanced UV-induced DNA damage.« less

UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins.

PubMed

Pacini, Laura; Ceraolo, Maria Grazia; Venuti, Assunta; Melita, Giusi; Hasan, Uzma A; Accardi, Rosita; Tommasino, Massimo

2017-10-01

Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist ΔNp73α, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis. IMPORTANCE Beta HPV types have been suggested to act as cofactors in UV-induced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation. Copyright © 2017 American Society for Microbiology.

Mechanism of UV-related carcinogenesis and its contribution to nevi/melanoma

PubMed Central

Anna, Brozyna; Blazej, Zbytek; Jacqueline, Granese; Andrew, Carlson J.; Jeffrey, Ross; Andrzej, Slominski

2008-01-01

Summary Melanoma consists 4–5 % of all skin cancers, but it contributes to 71–80 % of skin cancers deaths. UV light affects cell and tissue homeostasis due to its damaging effects on DNA integrity and modification of expression of a plethora of genes. DNA repair systems protect cells from UV-induced lesions. Several animal models of melanoma have been developed (Xiphophorus, Opossum Monodelphis domestica, mouse models and human skin engrafts into other animals). This review discusses possible links between UV and genes significantly related to melanoma but does not discuss melanoma genetics. These include oncogenes, tumor suppressor genes, genes related to melanocyte-keratinocyte and melanocyte-matrix interaction, growth factors and their receptors, CRH, ACTH, α-MSH, glucocorticoids, ID1, NF-kappaB and vitamin D3. PMID:18846265

Photodamage: all signs lead to actinic keratosis and early squamous cell carcinoma.

PubMed

Wei, Jerry; Kok, Lai Fong; Byrne, Scott N; Halliday, Gary M

2015-01-01

Ultraviolet (UV) radiation is likely to drive the initiation and progression of skin cancer from actinic keratosis to squamous cell carcinoma. Signs of photodamage occur at multiple steps. UV radiation damages many cellular constituents, including lipids, proteins and DNA, all of which are likely to contribute to UV-induced skin cancer. Two biological events culminating from photodamage are mutations in the genes critical to the control of cell division, differentiation and invasion and immunosuppression. DNA photodamage, if unrepaired prior to cell division, can result in the incorporation of an incorrect nucleotide into newly synthesised DNA. Mutations in critical genes contribute to carcinogenesis. Photodamage to proteins such as those involved in DNA repair or proteins or lipids involved in cellular signalling can interfere with this repair process and contribute to mutagenesis. Mutations in key genes, including TP53, BRM, PTCH1, and HRAS, contribute to skin carcinogenesis. UV also damages immunity. Photodamage to DNA and signalling lipids as well as other molecular changes are detrimental to the key cells that regulate immunity. Photodamaged dendritic cells and altered responses by mast cells lead to the activation of T and B regulatory cells that suppress immunity to the protein products of UV-mutated genes. This stops the immune response from its protective function of destroying mutated cells, enabling the transformed cells to progress to skin cancer. UV appears to play a pivotal role at each of these steps, and therefore, signs of photodamage point to the development of skin cancer. © 2015 S. Karger AG, Basel.

Molecular mechanisms of green tea polyphenols with protective effects against skin photoaging.

PubMed

Roh, Eunmiri; Kim, Jong-Eun; Kwon, Jung Yeon; Park, Jun Seong; Bode, Ann M; Dong, Zigang; Lee, Ki Won

2017-05-24

Whereas green tea has historically been consumed in high quantities in Northeast Asia, its popularity is also increasing in many Western countries. Green tea is an abundant source of plant polyphenols exhibiting numerous effects that are potentially beneficial for human health. Accumulating evidence suggests that green tea polyphenols confer protective effects on the skin against ultraviolet (UV) irradiation-induced acceleration of skin aging, involving antimelanogenic, antiwrinkle, antioxidant, and anti-inflammatory effects as well as prevention of immunosuppression. Melanin pigmentation in the skin is a major defense mechanism against UV irradiation, but pigmentation abnormalities such as melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation can also cause serious health and aesthetic issues. Furthermore, UV irradiation initiates the degradation of fibrillar collagen and elastic fibers, promoting the process of skin aging through deep wrinkle formation and loss of tissue elasticity. UV irradiation-induced formation of free radicals also contributes to accelerated photoaging. Additionally, immunosuppression caused by UV irradiation plays an important role in photoaging and skin carcinogenesis. In this review, we summarize the current literature regarding the antimelanogenic, antiwrinkle, antioxidant, and immunosuppression preventive mechanisms of green tea polyphenols that have been demonstrated to protect against UV irradiation-stimulated skin photoaging, and gauge the quality of evidence supporting the need for clinical studies using green tea polyphenols as anti-photoaging agents in novel cosmeceuticals.

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice.

PubMed

Mogensen, Mette; Jemec, Gregor Be

2010-10-28

In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice. A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers. Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior. The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers.

The potential carcinogenic risk of tanning beds: clinical guidelines and patient safety advice

PubMed Central

Mogensen, Mette; Jemec, Gregor BE

2010-01-01

Introduction: In 2009, the WHO listed ultraviolet (UV) radiation as a group 1 carcinogen. In spite of this, each year, millions of people tan indoor in Western countries. The aim of this review is to summarize evidence of tanning bed carcinogenesis and to present guidelines for use of tanning beds and patient safety advice. Methods: A narrative review of the literature was conducted based on both PubMed and Medline searches and on literature review of the retrieved papers. Results: Use of indoor tanning beds represents a significant and avoidable risk factor for the development of both melanoma and nonmelanoma skin cancers. Frequent tanners are more often adolescent females. Tanning beds have additional potential adverse effects such as burns, solar skin damage, infection, and possibly also addictive behavior. Discussion: The effort in preventing UV light-induced carcinogenesis should currently be aimed at developing new strategies for public health information. Tanning beds are one preventable source of UV radiation. In the majority of people solar UV radiation continues to be the major factor and therefore anti-tanning campaigns must always include sunbathers. PMID:21188119

An immunohistochemical panel to assess ultraviolet radiation-associated oxidative skin injury.

PubMed

Mamalis, A; Fiadorchanka, N; Adams, L; Serravallo, M; Heilman, E; Siegel, D; Brody, N; Jagdeo, J

2014-05-01

Ultraviolet (UV) radiation results in a significant loss in years of healthy life, approximately 1.5 million disability-adjusted life years (DALYs), and is associated with greater than 60,000 deaths annually worldwide that are attributed to melanoma and other skin cancers. Currently, there are no standardized biomarkers or assay panels to assess oxidative stress skin injury patterns in human skin exposed to ionizing radiation. Using biopsy specimens from chronic solar UV-exposed and UV-protected skin, we demonstrate that UV radiation-induced oxidative skin injury can be evaluated by an immunohistochemical panel that stains 8-hydroxydeoxyguanosine (8-OH-dG) to assess DNA adducts, 4-hydroxy-2-nonenal (HNE) to assess lipid peroxidation, and advanced glycation end products (AGEs) to assess protein damage. We believe this panel contains the necessary cellular biomarkers to evaluate topical agents, such as sunscreens and anti-oxidants that are designed to prevent oxidative skin damage and may reduce UV-associated skin aging, carcinogenesis, and inflammatory skin diseases. We envision that this panel will become an important tool for researchers developing topical agents to protect against UV radiation and other oxidants and ultimately lead to reductions in lost years of healthy life, DALYs, and annual deaths associated with UV radiation.

The Role of AKT/mTOR Pathway in Stress Response to UV-Irradiation: Implication in Skin Carcinogenesis by Regulation of Apoptosis, Autophagy and Senescence

PubMed Central

Strozyk, Elwira; Kulms, Dagmar

2013-01-01

Induction of DNA damage by UVB and UVA radiation may generate mutations and genomic instability leading to carcinogenesis. Therefore, skin cells being repeatedly exposed to ultraviolet (UV) light have acquired multilayered protective mechanisms to avoid malignant transformation. Besides extensive DNA repair mechanisms, the damaged skin cells can be eliminated by induction of apoptosis, which is mediated through the action of tumor suppressor p53. In order to prevent the excessive loss of skin cells and to maintain the skin barrier function, apoptotic pathways are counteracted by anti-apoptotic signaling including the AKT/mTOR pathway. However, AKT/mTOR not only prevents cell death, but is also active in cell cycle transition and hyper-proliferation, thereby also counteracting p53. In turn, AKT/mTOR is tuned down by the negative regulators being controlled by the p53. This inhibition of AKT/mTOR, in combination with transactivation of damage-regulated autophagy modulators, guides the p53-mediated elimination of damaged cellular components by autophagic clearance. Alternatively, p53 irreversibly blocks cell cycle progression to prevent AKT/mTOR-driven proliferation, thereby inducing premature senescence. Conclusively, AKT/mTOR via an extensive cross talk with p53 influences the UV response in the skin with no black and white scenario deciding over death or survival. PMID:23887651

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

PubMed

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 Circadian Clock Controls Sunburn Apoptosis and Erythema in Mouse Skin

PubMed Central

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

2014-01-01

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 Atr-mediated DNA damage checkpoint signaling including activation of the tumor suppressor p53, which is known to control the process of sunburn apoptosis. To our knowledge these data provide the first evidence that the circadian clock plays an important role in the erythemal response in UV-irradiated skin. The early morning is when DNA repair is at a minimum, 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. PMID:25431853

Fernblock (Polypodium leucotomos Extract): Molecular Mechanisms and Pleiotropic Effects in Light-Related Skin Conditions, Photoaging and Skin Cancers, a Review

PubMed Central

Parrado, Concepcion; Mascaraque, Marta; Gilaberte, Yolanda; Juarranz, Angeles; Gonzalez, Salvador

2016-01-01

Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity are emerging as novel method of photoprotection. Polypodium leucotomos extract (PL, commercial name Fernblock®, IFC Group, Spain) is a powerful antioxidant due to its high content of phenolic compounds. PL is administered orally, with proven safety, and it can also be used topically. Its mechanisms include inhibition of the generation and release of reactive oxygen species (ROS) by ultraviolet (UV) light. It also prevents UV- and ROS-induced DNA damage with inhibition of AP1 and NF-κB and protection of natural antioxidant enzyme systems. At the cellular level, PL decreases cellular apoptosis and necrosis mediated UV and inhibits abnormal extracellular matrix remodeling. PL reduces inflammation, prevents immunosuppression, activates tumor suppressor p53 and inhibits UV-induced cyclooxygenase-2 (COX-2) enzyme expression. In agreement with increased p53 activity, PL decreased UV radiation-induced cell proliferation. PL also prevents common deletions mitochondrial DNA damage induced by UVA, and MMP-1 expression induced Visible Light and Infrared Radiation. These cellular and molecular effects are reflected in inhibitions of carcinogenesis and photoaging. PMID:27367679

Fernblock (Polypodium leucotomos Extract): Molecular Mechanisms and Pleiotropic Effects in Light-Related Skin Conditions, Photoaging and Skin Cancers, a Review.

PubMed

Parrado, Concepcion; Mascaraque, Marta; Gilaberte, Yolanda; Juarranz, Angeles; Gonzalez, Salvador

2016-06-29

Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity are emerging as novel method of photoprotection. Polypodium leucotomos extract (PL, commercial name Fernblock(®), IFC Group, Spain) is a powerful antioxidant due to its high content of phenolic compounds. PL is administered orally, with proven safety, and it can also be used topically. Its mechanisms include inhibition of the generation and release of reactive oxygen species (ROS) by ultraviolet (UV) light. It also prevents UV- and ROS-induced DNA damage with inhibition of AP1 and NF-κB and protection of natural antioxidant enzyme systems. At the cellular level, PL decreases cellular apoptosis and necrosis mediated UV and inhibits abnormal extracellular matrix remodeling. PL reduces inflammation, prevents immunosuppression, activates tumor suppressor p53 and inhibits UV-induced cyclooxygenase-2 (COX-2) enzyme expression. In agreement with increased p53 activity, PL decreased UV radiation-induced cell proliferation. PL also prevents common deletions mitochondrial DNA damage induced by UVA, and MMP-1 expression induced Visible Light and Infrared Radiation. These cellular and molecular effects are reflected in inhibitions of carcinogenesis and photoaging.

A UV-independent pathway to melanoma carcinogenesis in the redhair-fairskin background

PubMed Central

Mitra, Devarati; Luo, Xi; Morgan, Ann; Wang, Jin; Hoang, Mai P.; Lo, Jennifer; Guerrero, Candace R.; Lennerz, Jochen K.; Mihm, Martin C.; Wargo, Jennifer A.; Robinson, Kathleen C.; Devi, Suprabha P.; Vanover, Jillian C.; D’Orazio, John A.; McMahon, Martin; Bosenberg, Marcus W.; Haigis, Kevin M.; Haber, Daniel A.; Wang, Yinsheng; Fisher, David E.

2012-01-01

People with pale skin, red hair, freckles, and an inability to tan—the “redhair/fairskin” phenotype— are at highest risk of developing melanoma, compared to all other pigmentation types1. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the Melanocortin 1 receptor (MC1R) gene. MC1R encodes a cAMP stimulating G-protein coupled receptor that controls pigment production. Minimal receptor activity, as in redhair/fairskin polymorphisms, produces red/yellow pheomelanin pigment, while increasing MC1R activity stimulates production of black/brown eumelanin2. Pheomelanin has weak UV shielding capacity relative to eumelanin and has been shown to amplify UVA-induced reactive oxygen species (ROS) 3–5. Several observations, however, complicate the assumption that melanoma risk is completely UV dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and UV signature mutations are infrequently oncogenic drivers6. While linkage of melanoma risk to UV exposure is beyond doubt, UV-independent events are also likely to play a significant role1,7. Here, we introduced into mice carrying an inactivating mutation in the Mc1r gene (who exhibit a phenotype analogous to redhair/fairskin humans), a conditional, melanocyte-targeted allele of the most commonly mutated melanoma oncogene, BRafV600E. We observed a high incidence of invasive melanomas without providing additional gene aberrations or UV exposure. To investigate the mechanism of UV-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/e mouse skin. These data suggest that the pheomelanin pigment pathway produces UV-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. While UV protection remains important, additional strategies may be required for optimal melanoma prevention. PMID:23123854

Low dose arsenite confers resistance to UV induced apoptosis via p53-MDM2 pathway in ketatinocytes

PubMed Central

Zhou, Y; Zeng, W; Qi, M; Duan, Y; Su, J; Zhao, S; Zhong, W; Gao, M; Li, F; He, Y; Hu, X; Xu, X; Chen, X; Peng, C; Zhang, J

2017-01-01

Chronic arsenite and ultraviolet (UV) exposure are associated with skin tumor. To investigate the details by low concentrations of arsenite and UV induced carcinogenesis in skin, hTERT-immortalized human keratinocytes were used as a cellular model with exposure to low concentrations of sodium arsenite and UV. The effect of NaAsO2 on UV treatment-induced apoptosis was measured by flow cytometry and Hoechst staining. We found that the cell apoptosis induced by UV exposure was significantly attenuated after exposure to low-dose arsenite, and knockdown of p53 could block UV-induced apoptosis indicating that this phenomenon depended on p53. Interestingly, the expression of murine double minute 2 (MDM2), including its protein and transcriptional levels, was remarkably high after exposure to low-dose arsenite. Moreover, low-dose arsenite treatment dramatically decreased the MDM2 gene promoter activity, suggesting that this effect has been mediated through transcription. In addition, treatment of PD98059 reversed low-dose arsenite-induced MDM2 expression, and the inhibition of ERK2 expression could significantly block MDM2 expression as a consequence, and p53 expression automatically was increased. To validate the role of p53 in exposure to low-dose arsenite, the expression of p53 was examined by immunohistochemistry in the skin of Sprague−Dawley rats model by chronic arsenite exposure for 6 months and in patients with arsenic keratosis, and the results showed that the expression of p53 was decreased in those samples. Taken together, our results demonstrated that low-dose arsenite-induced resistance to apoptosis through p53 mediated by MDM2 in keratinocytes. PMID:28785074

Effects of retinoids on ultraviolet-induced carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Epstein, J.H.

The evidence for effects of the retinoids on UV-induced carcinogenesis is sparse. Clinical observations indicate that topical RA can cause significant regression of premalignant actinic keratoses. Also there is some evidence that this agent can cause dissolution of some basal cell epitheliomas. However this latter effect does not appear to be of therapeutic value. Systemic retinoids are of little value in the treatment of premalignant and malignant cutaneous lesions though 13-cis-retinoic acid might be of use in the basal cell nevus syndrome. Examination of the influence of the retinoids on photocarcinogenesis essentially has been confined to RA and animal experimentation.more » RA in nontoxic concentrations can both stimulate and inhibit photocarcinogenesis depending upon the circumstances of the study. The mechanisms of these responses are not clear. Influences on DNA synthesis directly and/or indirectly or on immune responses may be involved in both effects. Preliminary studies with oral 13-cis-retinoic acid have not demonstrated any effects to date on UV-induced skin cancer formation.« less

Silver nanoparticles protect human keratinocytes against UVB radiation-induced DNA damage and apoptosis: potential for prevention of skin carcinogenesis

PubMed Central

Arora, Sumit; Tyagi, Nikhil; Bhardwaj, Arun; Rusu, Lilia; Palanki, Rohan; Vig, Komal; Singh, Shree R.; Singh, Ajay P.; Palanki, Srinivas; Miller, Michael E.; Carter, James E.; Singh, Seema

2015-01-01

Ultraviolet (UV)-B radiation from the sun is an established etiological cause of skin cancer, which afflicts more than a million lives each year in the United States alone. Here, we tested the chemopreventive efficacy of silver-nanoparticles (AgNPs) against UVB-irradiation-induced DNA damage and apoptosis in human immortalized keratinocytes (HaCaT). AgNPs were synthesized by reduction-chemistry and characterized for their physicochemical properties. AgNPs were well tolerated by HaCaT cells and their pretreatment protected them from UVB-irradiation-induced apoptosis along with significant reduction in cyclobutane-pyrimidine-dimer formation. Moreover, AgNPs pre-treatment led to G1-phase cell-cycle arrest in UVB-irradiated HaCaT cells. AgNPs were efficiently internalized in UVB-irradiated cells and localized into cytoplasmic and nuclear compartments. Furthermore, we observed an altered expression of various genes involved in cell-cycle, apoptosis and nucleotide-excision repair in HaCaT cells treated with AgNPs prior to UVB-irradiation. Together, these findings provide support for potential utility of AgNPs as novel chemopreventive agents against UVB-irradiation-induced skin carcinogenesis. PMID:25804413

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin.

PubMed

Kemp, Michael G; Spandau, Dan F; Travers, Jeffrey B

2017-02-26

The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin

PubMed Central

Kemp, Michael G.; Spandau, Dan F; Travers, Jeffrey B.

2017-01-01

The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC. PMID:28245638

Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin.

PubMed

Camouse, Melissa M; Domingo, Diana Santo; Swain, Freddie R; Conrad, Edward P; Matsui, Mary S; Maes, Daniel; Declercq, Lieve; Cooper, Kevin D; Stevens, Seth R; Baron, Elma D

2009-06-01

Tea polyphenols have been found to exert beneficial effects on the skin via their antioxidant properties. We sought to determine whether topical application of green tea or white tea extracts would prevent simulated solar radiation-induced oxidative damages to DNA and Langerhans cells that may lead to immune suppression and carcinogenesis. Skin samples were analysed from volunteers or skin explants treated with white tea or green tea after UV irradiation. In another group of patients, the in vivo immune protective effects of green and white tea were evaluated using contact hypersensitivity to dinitrochlorobenzene. Topical application of green and white tea offered protection against detrimental effects of UV on cutaneous immunity. Such protection is not because of direct UV absorption or sunscreen effects as both products showed a sun protection factor of 1. There was no significant difference in the levels of protection afforded by the two agents. Hence, both green tea and white tea are potential photoprotective agents that may be used in conjunction with established methods of sun protection.

[Role of cosmetics in environmental carcinogenesis].

PubMed

Riboulet-Delmas, G

1983-09-01

Cosmetics, which have been used for millenaries, have undergone a dramatic development since the last war. Conjointly with this development, cosmetology has entered a new, scientific, phase. A few facts will enable us to define the role of carcinogens in environmental carcinogenesis: first, by trying to determine what protection is given to the consumer against the carcinogenic risk; then, by delineating the protection provided by sunscreen agents against skin carcinomas induced by sun. Protection provided to consumers: physicochemical characteristics; Ames test for screening; animal experimentation; epidemiological studies; follow-up of products. Prevention of UV-dependent skin cancer; induction of skin tumors by sun; prevention. Individual factors which modulate these risks: Two examples: permeability of the psoriatic skin; morphotypes and sun. Given the present state of our knowledge, it seems inconceivable to achieve stricter scientific standards before marketing a product. One step is, and always will be, lacking for the evaluation of the noxiousness of a substance, i.e. its large scale, longterm evaluation in man, with allowances for biologic inequalities. This underscores the value of producer's daily vigilance, a vigilance which in fact concerns both the producer and the consumer.

Blue light-induced oxidative stress in live skin.

PubMed

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.

Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis.

PubMed

Kataoka, Ken; Kim, Dae Joon; Carbajal, Steve; Clifford, John L; DiGiovanni, John

2008-06-01

Constitutive activation of signal transducer and activator of transcription 3 (Stat3) has been found in a variety of human malignancies and has been suggested to play an important role in carcinogenesis. Recently, our laboratory demonstrated that Stat3 is required for the development of skin tumors via two-stage carcinogenesis using skin-specific loss-of-function transgenic mice. To investigate further the role of Stat3 in each stage of chemical carcinogenesis in mouse skin, i.e. initiation and promotion stages, we generated inducible Stat3-deficient mice (K5.Cre-ER(T2) x Stat3(fl/fl)) that show epidermal-specific disruption of Stat3 following topical treatment with 4-hydroxytamoxifen (TM). The epidermis of inducible Stat3-deficient mice treated with TM showed a significant increase in apoptosis induced by 7,12-dimethylbenz[a]anthracene (DMBA) and reduced proliferation following exposure to 12-O-tetradecanoylphorbol-13-acetate. In two-stage skin carcinogenesis assays, inducible Stat3-deficient mice treated with TM during the promotion stage showed a significant delay of tumor development and a significantly reduced number of tumors compared with control groups. Inducible Stat3-deficient mice treated with TM before initiation with DMBA also showed a significant delay in tumor development and a significantly reduced number of tumors compared with control groups. Finally, treatment of inducible Stat3-deficient mice that had existing skin tumors generated by the two-stage carcinogenesis protocol with TM (by intraperitoneal injection) led to inhibition of tumor growth compared with tumors formed in control groups. Collectively, these results directly demonstrate that Stat3 is required for skin tumor development during both the initiation and promotion stages of skin carcinogenesis in vivo.

NADPH Oxidase-1 Plays a Key Role in Keratinocyte Responses to UV Radiation and UVB-Induced Skin Carcinogenesis.

PubMed

Raad, Houssam; Serrano-Sanchez, Martin; Harfouche, Ghida; Mahfouf, Walid; Bortolotto, Doriane; Bergeron, Vanessa; Kasraian, Zeinab; Dousset, Lea; Hosseini, Mohsen; Taieb, Alain; Rezvani, Hamid Reza

2017-06-01

The nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes are involved in several physiological functions. However, their roles in keratinocyte responses to UV radiation have not been clearly elucidated. This study shows that, among other NOX family members, UVB irradiation results in a biphasic activation of NOX1 that plays a critical role in defining keratinocyte fate through the modulation of the DNA damage response network. Indeed, suppression of both bursts of UVB-induced NOX1 activation by using a specific peptide inhibitor of NOX1 (InhNOX1) is associated with increased nucleotide excision repair efficiency and reduction of apoptosis, which is finally translated into decreased photocarcinogenesis. On the contrary, when only the second peak of UVB-induced NOX1 activation is blocked, both nucleotide excision repair efficiency and apoptosis are decreased. Our results show that inhibition of NOX1 activation could be a promising target for the prevention and treatment of UVB-induced skin cancer in nucleotide excision repair-proficient and -deficient patients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Impaired spermatogenesis and elevated spontaneous tumorigenesis in xeroderma pigmentosum group A gene (Xpa)-deficient mice

PubMed Central

Nakane, Hironobu; Hirota, Seiichi; Brooks, Philip J.; Nakabeppu, Yusaku; Nakatsu, Yoshimichi; Nishimune, Yoshitake; Iino, Akihiro; Tanaka, Kiyoji

2009-01-01

We have reported that xeroderma pigmentosum group A (Xpa) gene-knockout mice [Xpa (−/−) mice] are deficient in nucleotide excision repair (NER) and highly sensitive to UV-induced skin carcinogenesis. Although xeroderma pigmentosum group A patients show growth retardation, immature sexual development, and neurological abnormalities as well as a high incidence of UV-induced skin tumors, Xpa (−/−) mice were physiologically and behaviorally normal. In the present study, we kept Xpa (−/−) mice for two years under specific pathogen-free (SPF) conditions and found that the testis diminished in an age-dependent manner, and degenerating seminiferous tubules and no spermatozoa were detected in the 24-month old Xpa (−/−) mice. In addition, a higher incidence of spontaneous tumorigenesis was observed in the 24-month old Xpa (−/−) mice compared to Xpa (+/+) controls. Xpa (−/−) mice provide a useful model for investigating the aging and internal tumor formation in XP-A patients. PMID:18790090

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice

PubMed Central

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A.; Xu, Hui; Katiyar, Santosh K.

2013-01-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DCs). Co-culture of CD4+ T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of Th-1 type cytokines that was ameliorated when the DCs were obtained from GSPs-fed mice; whereas, DCs obtained from GSPs-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4, dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. PMID:23321928

Sunlight Effects on Immune System: Is There Something Else in addition to UV-Induced Immunosuppression?

PubMed Central

Paz, M. L.; Leoni, J.

2016-01-01

Sunlight, composed of different types of radiation, including ultraviolet wavelengths, is an essential source of light and warmth for life on earth but has strong negative effects on human health, such as promoting the malignant transformation of skin cells and suppressing the ability of the human immune system to efficiently detect and attack malignant cells. UV-induced immunosuppression has been extensively studied since it was first described by Dr. Kripke and Dr. Fisher in the late 1970s. However, skin exposure to sunlight has not only this and other unfavorable effects, for example, mutagenesis and carcinogenesis, but also a positive one: the induction of Vitamin D synthesis, which performs several roles within the immune system in addition to favoring bone homeostasis. The impact of low levels of UV exposure on the immune system has not been fully reported yet, but it bears interesting differences with the suppressive effect of high levels of UV radiation, as shown by some recent studies. The aim of this article is to put some ideas in perspective and pose some questions within the field of photoimmunology based on established and new information, which may lead to new experimental approaches and, eventually, to a better understanding of the effects of sunlight on the human immune system. PMID:28070504

Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis.

PubMed

Antsiferova, Maria; Martin, Caroline; Huber, Marcel; Feyerabend, Thorsten B; Förster, Anja; Hartmann, Karin; Rodewald, Hans-Reimer; Hohl, Daniel; Werner, Sabine

2013-12-15

The growth and differentiation factor activin A is a key regulator of tissue repair, inflammation, fibrosis, and tumorigenesis. However, the cellular targets, which mediate the different activin functions, are still largely unknown. In this study, we show that activin increases the number of mature mast cells in mouse skin in vivo. To determine the relevance of this finding for wound healing and skin carcinogenesis, we mated activin transgenic mice with CreMaster mice, which are characterized by Cre recombinase-mediated mast cell eradication. Using single- and double-mutant mice, we show that loss of mast cells neither affected the stimulatory effect of overexpressed activin on granulation tissue formation and reepithelialization of skin wounds nor its protumorigenic activity in a model of chemically induced skin carcinogenesis. Furthermore, mast cell deficiency did not alter wounding-induced inflammation and new tissue formation or chemically induced angiogenesis and tumorigenesis in mice with normal activin levels. These findings reveal that mast cells are not major targets of activin during wound healing and skin cancer development and also argue against nonredundant functions of mast cells in wound healing and skin carcinogenesis in general.

A Topical Mitochondria-Targeted Redox Cycling Nitroxide Mitigates Oxidative Stress Induced Skin Damage

PubMed Central

Brand, Rhonda M.; Epperly, Michael W.; Stottlemyer, J. Mark; Skoda, Erin M.; Gao, Xiang; Li, Song; Huq, Saiful; Wipf, Peter; Kagan, Valerian E.; Greenberger, Joel S.; Falo, Louis D.

2017-01-01

Skin is the largest human organ and provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental stressor. Radiation induced skin damage ranges from photoaging and cutaneous carcinogenesis from UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species (ROS). Mitochondria are particularly susceptible to oxidative stress, and mitochondrial dependent apoptosis plays a major role in radiation induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent ROS accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrial targeted antioxidant prevents and mitigates radiation induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin’s antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress. PMID:27794421

Thrombospondin-2 overexpression in the skin of transgenic mice reduces the susceptibility to chemically induced multistep skin carcinogenesis.

PubMed

Kunstfeld, Rainer; Hawighorst, Thomas; Streit, Michael; Hong, Young-Kwon; Nguyen, Lynh; Brown, Lawrence F; Detmar, Michael

2014-05-01

We have previously reported stromal upregulation of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, and we found accelerated and enhanced skin angiogenesis and carcinogenesis in TSP-2 deficient mice. To investigate whether enhanced levels of TSP-2 might protect from skin cancer development. We established transgenic mice with targeted overexpression of TSP-2 in the skin and subjected hemizygous TSP-2 transgenic mice and their wild-type littermates to a chemical skin carcinogenesis regimen. TSP-2 transgenic mice showed a significantly delayed onset of tumor formation compared to wild-type mice, whereas the ratio of malignant conversion to squamous cell carcinomas was comparable in both genotypes. Computer-assisted morphometric analysis of blood vessels revealed pronounced tumor angiogenesis already in the early stages of carcinogenesis in wild type mice. TSP-2 overexpression significantly reduced tumor blood vessel density in transgenic mice but had no overt effect on LYVE-1 positive lymphatic vessels. The percentage of desmin surrounded, mature tumor-associated blood vessels and the degree of epithelial differentiation remained unaffected. The antiangiogenic effect of transgenic TSP-2 was accompanied by a significantly increased number of apoptotic tumor cells in transgenic mice. Our results demonstrate that enhanced levels of TSP-2 in the skin result in reduced susceptibility to chemically-induced skin carcinogenesis and identify TSP-2 as a new target for the prevention of skin cancer. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

The immune system and skin cancer.

PubMed

Yu, Sherry H; Bordeaux, Jeremy S; Baron, Elma D

2014-01-01

Carcinogenesis involves multiple mechanisms that disturb genomic integrity and encourage abnormal proliferation. The immune system plays an integral role in maintaining homeostasis and these mechanisms may arrest or enhance dysplasia. There exists a large body of evidence from organ transplantation literature supporting the significance of the immune suppression in the development of skin cancer. Nonmelanoma skin cancers are the most frequent neoplasms after organ transplantation, with organ transplant recipients having a 65-fold increase in squamous cell carcinoma incidence and 10-fold increase in basal cell carcinoma incidence. Similarly, UV-radiation (UVR) induced immunosuppression is correlated with the development of cutaneous malignancies in a dose-dependent manner. This was first shown several decades ago by Margaret Kripke, when transplanted tumors were rejected in mice with competent immune systems, but grew unchecked in immunosuppressed specimens. After UV exposure, chromophores initiate a cascade that leads to immunosuppression via derangement of Langerhans cells' antigen-presenting capacity. UV-irradiated Langerhans cells present antigens to Th2 cells, but fail to stimulate Th1 cells. A subset of T regulatory cells, specific for the antigen encountered after UVR, is also stimulated to proliferate. In general UV irradiation leads to a greater number of T regulatory cells and fewer effector T cells in the skin, shiftingthe balance from T-cell-mediated immunity to immunosuppression. These regulatory cells have the phenotype CD4+, CD25+, Foxp3+, CTLA-4+. These and many other changes in local immunity lead to a suppressed immune state, which allow for skin cancer development.

Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation

PubMed Central

Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

2015-01-01

The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis. PMID:25961580

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice.

PubMed

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A; Xu, Hui; Katiyar, Santosh K

2013-03-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4(+) T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242-52. ©2013 AACR. ©2013 AACR.

The protective effect of some Thai plants and their bioactive compounds in UV light-induced skin carcinogenesis.

PubMed

de Silva, Madhura B; Tencomnao, Tewin

2018-05-02

Skin cancer, represents a major public health concern. While the vast majority is non-melanoma skin cancers, melanomas are mostly responsible for mortality. Solar UVB radiation is mutagenic and carcinogenic. It is primarily responsible for both non-melanoma and melanoma skin cancers via excessive production of reactive oxygen species (ROS), which mediate changes in inflammation and immunity, and have been implicated in all three stages of skin cancer development. Due to their regulatory role in numerous functions of cells, signaling pathways are targets for chemoprevention. The current standards in melanoma therapy are targeted and combination therapies, which, albeit prolong survival responses, are still prone to development of drug resistance. To this extent, drugs of natural origin continue to spark great interest. Thailand has a rich biodiversity of indigenous flora, which have traditionally been used to treat a variety of pathologies. The active components in plant extracts that have medicinal properties, termed 'bioactive compounds,' are efficient chemopreventive agents due to their antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification properties. Thai plants and their bioactive compounds have shown protective effects on UV light-induced skin cancer in different experimental models. This warrants further in vivo investigations and translation to clinical studies to determine efficacy and safety, for use as lead compounds in targeted/combination therapy or adjuvant therapy with existing regimes. Coupled with a strategy for prevention, this offers a promising outlook for protection against photocarcinogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

Natural Antioxidants: Multiple Mechanisms to Protect Skin From Solar Radiation

PubMed Central

Dunaway, Spencer; Odin, Rachel; Zhou, Linli; Ji, Liyuan; Zhang, Yuhang; Kadekaro, Ana L.

2018-01-01

Human skin exposed to solar ultraviolet radiation (UVR) results in a dramatic increase in the production of reactive oxygen species (ROS). The sudden increase in ROS shifts the natural balance toward a pro-oxidative state, resulting in oxidative stress. The detrimental effects of oxidative stress occur through multiple mechanisms that involve alterations to proteins and lipids, induction of inflammation, immunosuppression, DNA damage, and activation of signaling pathways that affect gene transcription, cell cycle, proliferation, and apoptosis. All of these alterations promote carcinogenesis and therefore, regulation of ROS levels is critical to the maintenance of normal skin homeostasis. Several botanical products have been found to exhibit potent antioxidant capacity and the ability to counteract UV-induced insults to the skin. These natural products exert their beneficial effects through multiple pathways, including some known to be negatively affected by solar UVR. Aging of the skin is also accelerated by UVR exposure, in particular UVA rays that penetrate deep into the epidermis and the dermis where it causes the degradation of collagen and elastin fibers via oxidative stress and activation of matrix metalloproteinases (MMPs). Because natural compounds are capable of attenuating some of the UV-induced aging effects in the skin, increased attention has been generated in the area of cosmetic sciences. The focus of this review is to cover the most prominent phytoproducts with potential to mitigate the deleterious effects of solar UVR and suitability for use in topical application. PMID:29740318

Nanoencapsulation of rice bran oil increases its protective effects against UVB radiation-induced skin injury in mice.

PubMed

Rigo, Lucas Almeida; da Silva, Cássia Regina; de Oliveira, Sara Marchesan; Cabreira, Thaíssa Nunes; de Bona da Silva, Cristiane; Ferreira, Juliano; Beck, Ruy Carlos Ruver

2015-06-01

Excessive UV-B radiation by sunlight produces inflammatory and oxidative damage of skin, which can lead to sunburn, photoaging, and cancer. This study evaluated whether nanoencapsulation improves the protective effects of rice bran oil against UVB radiation-induced skin damage in mice. Lipid-core nanocapsules containing rice bran oil were prepared, and had mean size around 200 nm, negative zeta potential (∼-9 mV), and low polydispersity index (<0.20). In order to allow application on the skin, a hydrogel containing the nanoencapsulated rice bran oil was prepared. This formulation was able to prevent ear edema induced by UVB irradiation by 60 ± 9%, when compared with a hydrogel containing LNC prepared with a mixture of medium chain triglycerides instead of rice bran oil. Protein carbonylation levels (biomarker of oxidative stress) and NF-κB nuclear translocation (biomarker of pro-inflammatory and carcinogenesis response) were reduced (81% and 87%, respectively) in animals treated with the hydrogel containing the nanoencapsulated rice bran oil. These in vivo results demonstrate the beneficial effects of nanoencapsulation to improve the protective properties of rice bran oil on skin damage caused by UVB exposure. Copyright © 2015 Elsevier B.V. All rights reserved.

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2

PubMed Central

Furue, Masutaka; Uchi, Hiroshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Chiba, Takahito; Ito, Takamichi; Nakahara, Takeshi; Tsuji, Gaku

2017-01-01

Skin is the outermost part of the body and is, thus, inevitably exposed to UV rays and environmental pollutants. Oxidative stress by these hazardous factors accelerates skin aging and induces skin inflammation and carcinogenesis. Aryl hydrocarbon receptors (AHRs) are chemical sensors that are abundantly expressed in epidermal keratinocytes and mediate the production of reactive oxygen species. To neutralize or minimize oxidative stress, the keratinocytes also express nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling. Notably, there is fine-tuned crosstalk between AHR and NRF2, which mutually increase or decrease their activation states. Many NRF2-mediated antioxidant phytochemicals are capable of up- and downmodulating AHR signaling. The precise mechanisms by which these phytochemicals differentially affect the AHR and NRF2 system remain largely unknown and warrant future investigation. PMID:28273792

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2.

PubMed

Furue, Masutaka; Uchi, Hiroshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Chiba, Takahito; Ito, Takamichi; Nakahara, Takeshi; Tsuji, Gaku

2017-03-03

Skin is the outermost part of the body and is, thus, inevitably exposed to UV rays and environmental pollutants. Oxidative stress by these hazardous factors accelerates skin aging and induces skin inflammation and carcinogenesis. Aryl hydrocarbon receptors (AHRs) are chemical sensors that are abundantly expressed in epidermal keratinocytes and mediate the production of reactive oxygen species. To neutralize or minimize oxidative stress, the keratinocytes also express nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling. Notably, there is fine-tuned crosstalk between AHR and NRF2, which mutually increase or decrease their activation states. Many NRF2-mediated antioxidant phytochemicals are capable of up- and downmodulating AHR signaling. The precise mechanisms by which these phytochemicals differentially affect the AHR and NRF2 system remain largely unknown and warrant future investigation.

Shedding light on proteins, nucleic acids, cells, humans and fish

NASA Technical Reports Server (NTRS)

Setlow, Richard B.

2002-01-01

I was trained as a physicist in graduate school. Hence, when I decided to go into the field of biophysics, it was natural that I concentrated on the effects of light on relatively simple biological systems, such as proteins. The wavelengths absorbed by the amino acid subunits of proteins are in the ultraviolet (UV). The wavelengths that affect the biological activities, the action spectra, also are in the UV, but are not necessarily parallel to the absorption spectra. Understanding these differences led me to investigate the action spectra for affecting nucleic acids, and the effects of UV on viruses and cells. The latter studies led me to the discovery of the important molecular nature of the damages affecting DNA (cyclobutane pyrimidine dimers) and to the discovery of nucleotide excision repair. Individuals with the genetic disease xeroderma pigmentosum (XP) are extraordinarily sensitive to sunlight-induced skin cancer. The finding, by James Cleaver, that their skin cells were defective in DNA repair strongly suggested that DNA damage was a key step in carcinogenesis. Such information was important for estimating the wavelengths in sunlight responsible for human skin cancer and for predicting the effects of ozone depletion on the incidence of non-melanoma skin cancer. It took experiments with backcross hybrid fish to call attention to the probable role of the longer UV wavelengths not absorbed by DNA in the induction of melanoma. These reflections trace the biophysicist's path from molecules to melanoma.

Arsenate and dimethylarsinic acid in drinking water did not affect DNA damage repair in urinary bladder transitional cells or micronuclei in bone marrow

EPA Science Inventory

Arsenic is a recognized human skin, lung, and urinary bladder carcinogen, and may act as a cocarcinogen in the urinary bladder (with cigarette smoking) and skin (with UV light exposure). Possible modes of action of arsenic carcinogenesis/cocarcinogenesis include induction of DNA ...

Local Melatoninergic System as the Protector of Skin Integrity

PubMed Central

Slominski, Andrzej T.; Kleszczyński, Konrad; Semak, Igor; Janjetovic, Zorica; Żmijewski, Michał A.; Kim, Tae-Kang; Slominski, Radomir M.; Reiter, Russel J.; Fischer, Tobias W.

2014-01-01

The human skin is not only a target for the protective actions of melatonin, but also a site of melatonin synthesis and metabolism, suggesting an important role for a local melatoninergic system in protection against ultraviolet radiation (UVR) induced damages. While melatonin exerts many effects on cell physiology and tissue homeostasis via membrane bound melatonin receptors, the strong protective effects of melatonin against the UVR-induced skin damage including DNA repair/protection seen at its high (pharmocological) concentrations indicate that these are mainly mediated through receptor-independent mechanisms or perhaps through activation of putative melatonin nuclear receptors. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. In summary, we propose that melatonin can be exploited therapeutically as a protective agent or as a survival factor with anti-genotoxic properties or as a “guardian” of the genome and cellular integrity with clinical applications in UVR-induced pathology that includes carcinogenesis and skin aging. PMID:25272227

History of UV Lamps, Types, and Their Applications.

PubMed

Ahmad, Shamim I; Christensen, Luisa; Baron, Elma

2017-01-01

The use of ultraviolet (UV) light, for the treatment of skin conditions, dates back to the early 1900s. It is well known that sunlight can be of therapeutic value, but it can also lead to deleterious effects such as burning and carcinogenesis. Extensive research has expanded our understanding of UV radiation and its effects in human systems and has led to the development of man-made UV sources that are more precise, safer, and more effective for the treatment of wide variety of dermatologic conditions.

Hereditary Disorders with Defective Repair of UV-Induced DNA Damage

PubMed Central

Moriwaki, Shinichi

2013-01-01

Nucleotide excision repair (NER) is an essential system for correcting ultraviolet (UV)—induced DNA damage. Lesions remaining in DNA due to reduced capacity of NER may result in cellular death, premature aging, mutagenesis and carcinogenesis of the skin. So, NER is an important protection against these changes. There are three representative genodermatoses resulting from genetic defects in NER: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). In Japan, CS is similarly rare but XP is more common and TTD is less common compared to Western countries. In 1998, we established the system for the diagnosis of these disorders and we have been performing DNA repair and genetic analysis for more than 400 samples since then. At present, there is no cure for any human genetic disorder. Early diagnosis and symptomatic treatment of neurological, ocular and dermatological abnormalities should contribute to prolonging life and elevating QOL in patients. PMID:23966815

An Evaluation of Root Phytochemicals Derived from Althea officinalis (Marshmallow) and Astragalus membranaceus as Potential Natural Components of UV Protecting Dermatological Formulations

PubMed Central

Curnow, Alison; Owen, Sara J.

2016-01-01

As lifetime exposure to ultraviolet (UV) radiation has risen, the deleterious effects have also become more apparent. Numerous sunscreen and skincare products have therefore been developed to help reduce the occurrence of sunburn, photoageing, and skin carcinogenesis. This has stimulated research into identifying new natural sources of effective skin protecting compounds. Alkaline single-cell gel electrophoresis (comet assay) was employed to assess aqueous extracts derived from soil or hydroponically glasshouse-grown roots of Althea officinalis (Marshmallow) and Astragalus membranaceus, compared with commercial, field-grown roots. Hydroponically grown root extracts from both plant species were found to significantly reduce UVA-induced DNA damage in cultured human lung and skin fibroblasts, although initial Astragalus experimentation detected some genotoxic effects, indicating that Althea root extracts may be better suited as potential constituents of dermatological formulations. Glasshouse-grown soil and hydroponic Althea root extracts afforded lung fibroblasts with statistically significant protection against UVA irradiation for a greater period of time than the commercial field-grown roots. No significant reduction in DNA damage was observed when total ultraviolet irradiation (including UVB) was employed (data not shown), indicating that the extracted phytochemicals predominantly protected against indirect UVA-induced oxidative stress. Althea phytochemical root extracts may therefore be useful components in dermatological formulations. PMID:26953144

An Evaluation of Root Phytochemicals Derived from Althea officinalis (Marshmallow) and Astragalus membranaceus as Potential Natural Components of UV Protecting Dermatological Formulations.

PubMed

Curnow, Alison; Owen, Sara J

2016-01-01

As lifetime exposure to ultraviolet (UV) radiation has risen, the deleterious effects have also become more apparent. Numerous sunscreen and skincare products have therefore been developed to help reduce the occurrence of sunburn, photoageing, and skin carcinogenesis. This has stimulated research into identifying new natural sources of effective skin protecting compounds. Alkaline single-cell gel electrophoresis (comet assay) was employed to assess aqueous extracts derived from soil or hydroponically glasshouse-grown roots of Althea officinalis (Marshmallow) and Astragalus membranaceus, compared with commercial, field-grown roots. Hydroponically grown root extracts from both plant species were found to significantly reduce UVA-induced DNA damage in cultured human lung and skin fibroblasts, although initial Astragalus experimentation detected some genotoxic effects, indicating that Althea root extracts may be better suited as potential constituents of dermatological formulations. Glasshouse-grown soil and hydroponic Althea root extracts afforded lung fibroblasts with statistically significant protection against UVA irradiation for a greater period of time than the commercial field-grown roots. No significant reduction in DNA damage was observed when total ultraviolet irradiation (including UVB) was employed (data not shown), indicating that the extracted phytochemicals predominantly protected against indirect UVA-induced oxidative stress. Althea phytochemical root extracts may therefore be useful components in dermatological formulations.

UV-Induced Molecular Signaling Differences in Melanoma and Non-melanoma Skin Cancer.

PubMed

Liu-Smith, Feng; Jia, Jinjing; Zheng, Yan

2017-01-01

There are three major types of skin cancer: melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC and SCC are often referred to as non-melanoma skin cancer (NMSC). NMSCs are relatively non-lethal and curable by surgery, hence are not reportable in most cancer registries all over the world. Melanoma is the deadliest skin cancer. Its incidence rate (case number) is about 1/10th of that for NMSC, yet its death toll is ~8 fold higher than NMSC.Melanomas arise from melanocytes which are normally located on the basement membrane with dendrites extending into the epidermal keratinocytes. A major known function of melanocytes is to produce pigments which are enclosed by lipid membrane (termed melanosomes) and distribute them into keratinocytes, thus give different shade of skin colors. BCCs arise from basal cells, which are a layer of cells located at the deepest part of epidermis. Basal cells are recently considered to be skin stem cells as they are constantly proliferating and generating keratinocytes which are continuously pushed to the surface and eventually become a dead layer of stratum corneum. Squamous cells are the keratinocytes which resembles fish scale shape, ie, those initiated from basal cells and differentiated into squamous cells. Both basal cells and squamous cells belong to keratinocytes, therefore sometimes BCC and SCC are termed keratinocyte cancer.These three types of cancer share many characteristics, yet they are very different from etiology to progression. One shared characteristic of skin cancer is that, according to the current views, they all are caused by solar or artificial ultraviolet radiation (UVR). UVA and UVB from solar UVR are the major UV bands reaching the earth surface. Both UV types cause DNA damage and immune suppression which play crucial roles in skin carcinogenesis. UVB can be directly absorbed by DNA molecules and thus causes UV-signature DNA damages; UVA, on the other hand, may function through inducing cellular ROS which then causes oxidative DNA damages [1-4]. This chapter will discuss the molecular signaling differences of UVR in melanoma and NMSC.

Gq protein mediates UVB-induced cyclooxygenase-2 expression by stimulating HB-EGF secretion from HaCaT human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, MiRan; Juhnn, Yong-Sung, E-mail: juhnn@snu.ac.kr

Ultraviolet (UV) radiation induces cyclooxygenase-2 expression to produce cellular responses including aging and carcinogenesis in skin. We hypothesised that heterotrimeric G proteins mediate UV-induced COX-2 expression by stimulating secretion of soluble HB-EGF (sHB-EGF). In this study, we aimed to elucidate the role and underlying mechanism of the {alpha} subunit of Gq protein (G{alpha}q) in UVB-induced HB-EGF secretion and COX-2 induction. We found that expression of constitutively active G{alpha}q (G{alpha}qQL) augmented UVB-induced HB-EGF secretion, which was abolished by knockdown of G{alpha}q with shRNA in HaCaT human keratinocytes. G{alpha}q was found to mediate the UVB-induced HB-EGF secretion by sequential activation of phospholipasemore » C (PLC), protein kinase C{delta} (PKC{delta}), and matrix metaloprotease-2 (MMP-2). Moreover, G{alpha}qQL mediated UVB-induced COX-2 expression in an HB-EGF-, EGFR-, and p38-dependent manner. From these results, we concluded that G{alpha}q mediates UV-induced COX-2 expression through activation of EGFR by HB-EGF, of which ectodomain shedding was stimulated through sequential activation of PLC, PKC{delta} and MMP-2 in HaCaT cells.« less

Protective Effect of Tropical Highland Blackberry Juice (Rubus adenotrichos Schltdl.) Against UVB-Mediated Damage in Human Epidermal Keratinocytes and in a Reconstituted Skin Equivalent Model

PubMed Central

Calvo-Castro, Laura; Syed, Deeba N.; Chamcheu, Jean C.; Vilela, Fernanda M. P.; Pérez, Ana M.; Vaillant, Fabrice; Rojas, Miguel; Mukhtar, Hasan

2014-01-01

Solar ultraviolet (UV) radiation, particularly its UVB (280–320 nm) spectrum, is the primary environmental stimulus leading to skin carcinogenesis. Several botanical species with antioxidant properties have shown photochemopreventive effects against UVB damage. Costa Rica’s tropical highland blackberry (Rubus adenotrichos) contains important levels of phenolic compounds, mainly ellagitannins and anthocyanins, with strong antioxidant properties. In this study, we examined the photochemopreventive effect of R. adenotrichos blackberry juice (BBJ) on UVB-mediated responses in human epidermal keratinocytes and in a three-dimensional (3D) reconstituted normal human skin equivalent (SE). Pretreatment (2 h) and posttreatment (24 h) of normal human epidermal keratinocytes (NHEKs) with BBJ reduced UVB (25 mJ cm−2)-mediated (1) cyclobutane pyrimidine dimers (CPDs) and (2) 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) formation. Furthermore, treatment of NHEKs with BBJ increased UVB-mediated (1) poly(ADP-ribose) polymerase cleavage and (2) activation of caspases 3, 8 and 9. Thus, BBJ seems to alleviate UVB-induced effects by reducing DNA damage and increasing apoptosis of damaged cells. To establish the in vivo significance of these findings to human skin, immunohistochemistry studies were performed in a 3D SE model, where BBJ was also found to decrease CPDs formation. These data suggest that BBJ may be developed as an agent to ameliorate UV-induced skin damage. PMID:23711186

Protective effect of tropical highland blackberry juice (Rubus adenotrichos Schltdl.) against UVB-mediated damage in human epidermal keratinocytes and in a reconstituted skin equivalent model.

PubMed

Calvo-Castro, Laura; Syed, Deeba N; Chamcheu, Jean C; Vilela, Fernanda M P; Pérez, Ana M; Vaillant, Fabrice; Rojas, Miguel; Mukhtar, Hasan

2013-01-01

Solar ultraviolet (UV) radiation, particularly its UVB (280-320 nm) spectrum, is the primary environmental stimulus leading to skin carcinogenesis. Several botanical species with antioxidant properties have shown photochemopreventive effects against UVB damage. Costa Rica's tropical highland blackberry (Rubus adenotrichos) contains important levels of phenolic compounds, mainly ellagitannins and anthocyanins, with strong antioxidant properties. In this study, we examined the photochemopreventive effect of R. adenotrichos blackberry juice (BBJ) on UVB-mediated responses in human epidermal keratinocytes and in a three-dimensional (3D) reconstituted normal human skin equivalent (SE). Pretreatment (2 h) and posttreatment (24 h) of normal human epidermal keratinocytes (NHEKs) with BBJ reduced UVB (25 mJ cm(-2))-mediated (1) cyclobutane pyrimidine dimers (CPDs) and (2) 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation. Furthermore, treatment of NHEKs with BBJ increased UVB-mediated (1) poly(ADP-ribose) polymerase cleavage and (2) activation of caspases 3, 8 and 9. Thus, BBJ seems to alleviate UVB-induced effects by reducing DNA damage and increasing apoptosis of damaged cells. To establish the in vivo significance of these findings to human skin, immunohistochemistry studies were performed in a 3D SE model, where BBJ was also found to decrease CPDs formation. These data suggest that BBJ may be developed as an agent to ameliorate UV-induced skin damage. © 2013 The American Society of Photobiology.

EFFECT OF ARSENICALS ON ULTRAVIOLET-RADIATION-INDUCED GROWTH ARREST AND RELATED SIGNALING EVENTS IN HUMAN KERATINOCYTES

EPA Science Inventory

The molecular mechanisms mediating arsenic-induced carcinogenesis are not well understood. The role of confounding factors such as ultraviolet radiation (UV), add another level of complexity to the study of arsenic carcinogenesis and the cancer risk assessment to humans. We hypot...

Gremlin inhibits UV-induced skin cell damages via activating VEGFR2-Nrf2 signaling

PubMed Central

Xu, Qiu-yun; Zhang, Jing; Lin, Meng-ting; Tu, Ying; He, Li; Bi, Zhi-gang; Cheng, Bo

2016-01-01

Ultra Violet (UV) radiation induces reactive oxygen species (ROS) production, DNA oxidation and single strand breaks (SSBs), which will eventually lead to skin cell damages or even skin cancer. Here, we tested the potential activity of gremlin, a novel vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) agonist, against UV-induced skin cell damages. We show that gremlin activated VEGFR2 and significantly inhibited UV-induced death and apoptosis of skin keratinocytes and fibroblasts. Pharmacological inhibition or shRNA-mediated knockdown of VEGFR2 almost abolished gremlin-mediated cytoprotection against UV in the skin cells. Further studies showed that gremlin activated VEGFR2 downstream NF-E2-related factor 2 (Nrf2) signaling, which appeared required for subsequent skin cell protection. Nrf2 shRNA knockdown or S40T dominant negative mutation largely inhibited gremlin-mediated skin cell protection against UV. At last, we show that gremlin dramatically inhibited UV-induced ROS production and DNA SSB formation in skin keratinocytes and fibroblasts. We conclude that gremlin protects skin cells from UV damages via activating VEGFR2-Nrf2 signaling. Gremlin could be further tested as a novel anti-UV skin protectant. PMID:27713170

Gremlin inhibits UV-induced skin cell damages via activating VEGFR2-Nrf2 signaling.

PubMed

Ji, Chao; Huang, Jin-Wen; Xu, Qiu-Yun; Zhang, Jing; Lin, Meng-Ting; Tu, Ying; He, Li; Bi, Zhi-Gang; Cheng, Bo

2016-12-20

Ultra Violet (UV) radiation induces reactive oxygen species (ROS) production, DNA oxidation and single strand breaks (SSBs), which will eventually lead to skin cell damages or even skin cancer. Here, we tested the potential activity of gremlin, a novel vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) agonist, against UV-induced skin cell damages. We show that gremlin activated VEGFR2 and significantly inhibited UV-induced death and apoptosis of skin keratinocytes and fibroblasts. Pharmacological inhibition or shRNA-mediated knockdown of VEGFR2 almost abolished gremlin-mediated cytoprotection against UV in the skin cells. Further studies showed that gremlin activated VEGFR2 downstream NF-E2-related factor 2 (Nrf2) signaling, which appeared required for subsequent skin cell protection. Nrf2 shRNA knockdown or S40T dominant negative mutation largely inhibited gremlin-mediated skin cell protection against UV. At last, we show that gremlin dramatically inhibited UV-induced ROS production and DNA SSB formation in skin keratinocytes and fibroblasts. We conclude that gremlin protects skin cells from UV damages via activating VEGFR2-Nrf2 signaling. Gremlin could be further tested as a novel anti-UV skin protectant.

UVA and UVB Irradiation Differentially Regulate microRNA Expression in Human Primary Keratinocytes

PubMed Central

Kraemer, Anne; Chen, I-Peng; Henning, Stefan; Faust, Alexandra; Volkmer, Beate; Atkinson, Michael J.; Moertl, Simone; Greinert, Ruediger

2013-01-01

MicroRNA (miRNA)-mediated regulation of the cellular transcriptome is an important epigenetic mechanism for fine-tuning regulatory pathways. These include processes related to skin cancer development, progression and metastasis. However, little is known about the role of microRNA as an intermediary in the carcinogenic processes following exposure to UV-radiation. We now show that UV irradiation of human primary keratinocytes modulates the expression of several cellular miRNAs. A common set of miRNAs was influenced by exposure to both UVA and UVB. However, each wavelength band also activated a distinct subset of miRNAs. Common sets of UVA- and UVB-regulated miRNAs harbor the regulatory elements GLYCA-nTRE, GATA-1-undefined-site-13 or Hox-2.3-undefined-site-2 in their promoters. In silico analysis indicates that the differentially expressed miRNAs responding to UV have potential functions in the cellular pathways of cell growth and proliferation. Interestingly, the expression of miR-23b, which is a differentiation marker of human keratinocytes, is remarkably up-regulated after UVA irradiation. Studying the interaction between miR-23b and its putative skin-relevant targets using a Luciferase reporter assay revealed that RRAS2 (related RAS viral oncogene homolog 2), which is strongly expressed in highly aggressive malignant skin cancer, to be a direct target of miR-23b. This study demonstrates for the first time a differential miRNA response to UVA and UVB in human primary keratinocytes. This suggests that selective regulation of signaling pathways occurs in response to different UV energies. This may shed new light on miRNA-regulated carcinogenic processes involved in UV-induced skin carcinogenesis. PMID:24391759

Photocarcinogenesis and Skin Cancer Prevention Strategies.

PubMed

Seebode, Christina; Lehmann, Janin; Emmert, Steffen

2016-03-01

In this review the basic principles of UV-induced carcinogenesis are summarized and the state of the art diagnosis and therapeutic strategies are discussed. The prevalent keratinocyte-derived neoplasms of the skin are basal cell and squamous cell carcinomas. Cutaneous melanoma is less frequent but associated with high mortality. Common risk factors for all three tumor entities include sun exposure and DNA-repair deficiencies. Photocarcinogenesis follows a multistep model of cancer development in which ultraviolet-induced DNA damage leads to mutations resulting in activation of oncogenes or silencing of tumor-suppressor genes. This ends in a cellular mutator phenotype even more prone to mutation acquisition. DNA repair, especially the nucleotide excision repair (NER) pathway, counteracts mutation formation and skin cancer development. This is vividly demonstrated by the NER-defective disorder xeroderma pigmentosum. Primary skin cancer preventative strategies, therefore, include reduction of DNA photodamage by protection from the sun. Secondary preventative strategies include skin cancer screening. This implies standard examination techniques with the naked eye, an epiluminescence microscope, or digital epiluminescence microscopy. More advanced techniques include confocal laser scan microscopy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemically induced skin carcinogenesis: Updates in experimental models (Review)

PubMed Central

NEAGU, MONICA; CARUNTU, CONSTANTIN; CONSTANTIN, CAROLINA; BODA, DANIEL; ZURAC, SABINA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

2016-01-01

Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.

PubMed

Aziz, Saba W; Aziz, Moammir H

2018-01-01

Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

PubMed

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.

A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes

PubMed Central

Dickinson, Sally E.; Olson, Erik R.; Levenson, Corey; Janda, Jaroslav; Rusche, Jadrian J.; Alberts, David S.; Bowden, G. Timothy

2014-01-01

One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt, or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer. PMID:25004464

A novel chemopreventive mechanism for a traditional medicine: East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes.

PubMed

Dickinson, Sally E; Olson, Erik R; Levenson, Corey; Janda, Jaroslav; Rusche, Jadrian J; Alberts, David S; Bowden, G Timothy

2014-09-15

One of the primary components of the East Indian sandalwood oil (EISO) is α-santalol, a molecule that has been investigated for its potential use as a chemopreventive agent in skin cancer. Although there is some evidence that α-santalol could be an effective chemopreventive agent, to date, purified EISO has not been extensively investigated even though it is widely used in cultures around the world for its health benefits as well as for its fragrance and as a cosmetic. In the current study, we show for the first time that EISO-treatment of HaCaT keratinocytes results in a blockade of cell cycle progression as well as a concentration-dependent inhibition of UV-induced AP-1 activity, two major cellular effects known to drive skin carcinogenesis. Unlike many chemopreventive agents, these effects were not mediated through an inhibition of signaling upstream of AP-1, as EISO treatment did not inhibit UV-induced Akt or MAPK activity. Low concentrations of EISO were found to induce HaCaT cell death, although not through apoptosis as annexin V and PARP cleavage were not found to increase with EISO treatment. However, plasma membrane integrity was severely compromised in EISO-treated cells, which may have led to cleavage of LC3 and the induction of autophagy. These effects were more pronounced in cells stimulated to proliferate with bovine pituitary extract and EGF prior to receiving EISO. Together, these effects suggest that EISO may exert beneficial effects upon skin, reducing the likelihood of promotion of pre-cancerous cells to actinic keratosis (AK) and skin cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model.

PubMed

Li, Wenjuan; Zhang, Chunjing; Du, Hongyan; Huang, Vincent; Sun, Brandi; Harris, John P; Richardson, Quitin; Shen, Xinggui; Jin, Rong; Li, Guohong; Kevil, Christopher G; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

2016-11-01

Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

PubMed

Yang, Bo; Xu, Qiu-Yun; Guo, Chun-Yan; Huang, Jin-Wen; Wang, Shu-Mei; Li, Yong-Mei; Tu, Ying; He, Li; Bi, Zhi-Gang; Ji, Chao; Cheng, Bo

2017-02-21

Ultra Violet (UV)-caused skin cell damage is a main cause of skin cancer. Here, we studied the activity of MHY1485, a mTOR activator, in UV-treated skin cells. In primary human skin keratinocytes, HaCaT keratinocytes and human skin fibroblasts, MHY1485 ameliorated UV-induced cell death and apoptosis. mTOR activation is required for MHY1485-induced above cytoprotective actions. mTOR kinase inhibitors (OSI-027, AZD-8055 and AZD-2014) or mTOR shRNA knockdown almost abolished MHY1485-induced cytoprotection. Further, MHY1485 treatment in skin cells activated mTOR downstream NF-E2-related factor 2 (Nrf2) signaling, causing Nrf2 Ser-40 phosphorylation, stabilization/upregulation and nuclear translocation, as well as mRNA expression of Nrf2-dictated genes. Contrarily, Nrf2 knockdown or S40T mutation almost nullified MHY1485-induced cytoprotection. MHY1485 suppressed UV-induced reactive oxygen species production and DNA single strand breaks in skin keratinocytes and fibroblasts. Together, we conclude that MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling.

P16 UV mutations in human skin epithelial tumors.

PubMed

Soufir, N; Molès, J P; Vilmer, C; Moch, C; Verola, O; Rivet, J; Tesniere, A; Dubertret, L; Basset-Seguin, N

1999-09-23

The p16 gene expresses two alternative transcripts (p16alpha and p16beta) involved in tumor suppression via the retinoblastoma (Rb) or p53 pathways. Disruption of these pathways can occur through inactivation of p16 or p53, or activating mutations of cyclin dependant kinase 4 gene (Cdk4). We searched for p16, Cdk4 and p53 gene mutations in 20 squamous cell carcinomas (SSCs), 1 actinic keratosis (AK), and 28 basal cell carcinomas (BCCs), using PCR-SSCP. A deletion and methylation analysis of p16 was also performed. Six different mutations (12%) were detected in exon 2 of p16 (common to p16alpha and p16beta), in five out of 21 squamous lesions (24%) (one AK and four SCCs) and one out of 28 BCCs (3.5%). These included four (66%) ultraviolet (UV)-type mutations (two tandems CC : GG to TT : AA transitions and two C : G to T : A transitions at dipyrimidic site) and two transversions. P53 mutations were present in 18 samples (37%), mostly of UV type. Of these, only two (one BCC and one AK) harboured simultaneously mutations of p16, but with no consequence on p16beta transcript. Our data demonstrate for the first time the presence of p16 UV induced mutations in non melanoma skin cancer, particularly in the most aggressive SCC type, and support that p16 and p53 are involved in two independent pathways in skin carcinogenesis.

Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2.

PubMed

Tao, Shasha; Park, Sophia L; Rojo de la Vega, Montserrat; Zhang, Donna D; Wondrak, Georg T

2015-12-01

Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and an urgent need exists for improved molecular photoprotective strategies different from (or synergistic with) photon absorption. Recent studies suggest a photoprotective role of cutaneous gene expression orchestrated by the transcription factor NRF2 (nuclear factor-E2-related factor 2). Here we have explored the molecular mechanism underlying carotenoid-based systemic skin photoprotection in SKH-1 mice and provide genetic evidence that photoprotection achieved by the FDA-approved apocarotenoid and food additive bixin depends on NRF2 activation. Bixin activates NRF2 through the critical Cys-151 sensor residue in KEAP1, orchestrating a broad cytoprotective response in cultured human keratinocytes as revealed by antioxidant gene expression array analysis. Following dose optimization studies for cutaneous NRF2 activation by systemic administration of bixin, feasibility of bixin-based suppression of acute cutaneous photodamage from solar UV exposure was investigated in Nrf2(+/+) versus Nrf2(-/-) SKH-1 mice. Systemic administration of bixin suppressed skin photodamage, attenuating epidermal oxidative DNA damage and inflammatory responses in Nrf2(+/+) but not in Nrf2(-/-) mice, confirming the NRF2-dependence of bixin-based cytoprotection. Taken together, these data demonstrate feasibility of achieving NRF2-dependent cutaneous photoprotection by systemic administration of the apocarotenoid bixin, a natural food additive consumed worldwide. Copyright © 2015 Elsevier Inc. All rights reserved.

Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention.

PubMed

Boakye, Cedar H A; Patel, Ketan; Doddapaneni, Ravi; Bagde, Arvind; Behl, Gautam; Chowdhury, Nusrat; Safe, Stephen; Singh, Mandip

2016-07-01

In this study, we developed cationic ultra-flexible nanocarriers (UltraFLEX-Nano) to surmount the skin barrier structure and to potentiate the topical delivery of a highly lipophilic antioxidative diindolylmethane derivative (DIM-D) for the inhibition of UV-induced DNA damage and skin carcinogenesis. UltraFLEX-Nano was prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol and tween-80 by ethanolic injection method; was characterized by Differential Scanning Calorimetric (DSC), Fourier Transform Infrared (FT-IR) and Atomic Force Microscopic (phase-imaging) analyses and permeation studies were performed in dermatomed human skin. The efficacy of DIM-D-UltraFLEX-Nano for skin cancer chemoprevention was evaluated in UVB-induced skin cancer model in vivo. DIM-D-UltraFLEX-Nano formed a stable mono-dispersion (110.50±0.71nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR and AFM phase imaging. The blank formulation was non-toxic to human embryonic kidney cells. UltraFLEX-Nano was vastly deformable and highly permeable across the stratum corneum; there was significant (p<0.01) skin deposition of DIM-D for UltraFLEX-Nano that was superior to PEG solution (13.83-fold). DIM-D-UltraFLEX-Nano pretreatment delayed the onset of UVB-induced tumorigenesis (2 weeks) and reduced (p<0.05) the number of tumors observed in SKH-1 mice (3.33-fold), which was comparable to pretreatment with sunscreen (SPF30). Also, DIM-D-UltraFLEX-Nano caused decrease (p<0.05) in UV-induced DNA damage (8-hydroxydeoxyguanosine), skin inflammation (PCNA), epidermal hyperplasia (c-myc, CyclinD1), immunosuppression (IL10), cell survival (AKT), metastasis (Vimentin, MMP-9, TIMP1) but increase in apoptosis (p53 and p21). UltraFLEX-Nano was efficient in enhancing the topical delivery of DIM-D. DIM-D-UltraFLEX-Nano was efficacious in delaying skin tumor incidence and multiplicity in SKH mice comparable to sunscreen (SPF30). Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

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.

MHY1485 ameliorates UV-induced skin cell damages via activating mTOR-Nrf2 signaling

PubMed Central

Yang, Bo; Xu, Qiu-Yun; Guo, Chun-Yan; Huang, Jin-Wen; Wang, Shu-Mei; Li, Yong-Mei; Tu, Ying; He, Li; Bi, Zhi-Gang; Ji, Chao; Cheng, Bo

2017-01-01

Ultra Violet (UV)-caused skin cell damage is a main cause of skin cancer. Here, we studied the activity of MHY1485, a mTOR activator, in UV-treated skin cells. In primary human skin keratinocytes, HaCaT keratinocytes and human skin fibroblasts, MHY1485 ameliorated UV-induced cell death and apoptosis. mTOR activation is required for MHY1485-induced above cytoprotective actions. mTOR kinase inhibitors (OSI-027, AZD-8055 and AZD-2014) or mTOR shRNA knockdown almost abolished MHY1485-induced cytoprotection. Further, MHY1485 treatment in skin cells activated mTOR downstream NF-E2-related factor 2 (Nrf2) signaling, causing Nrf2 Ser-40 phosphorylation, stabilization/upregulation and nuclear translocation, as well as mRNA expression of Nrf2-dictated genes. Contrarily, Nrf2 knockdown or S40T mutation almost nullified MHY1485-induced cytoprotection. MHY1485 suppressed UV-induced reactive oxygen species production and DNA single strand breaks in skin keratinocytes and fibroblasts. Together, we conclude that MHY1485 inhibits UV-induced skin cell damages via activating mTOR-Nrf2 signaling. PMID:28061443

Atomic hydrogen surrounded by water molecules, H(H2O)m, modulates basal and UV-induced gene expressions in human skin in vivo.

PubMed

Shin, Mi Hee; Park, Raeeun; Nojima, Hideo; Kim, Hyung-Chel; Kim, Yeon Kyung; Chung, Jin Ho

2013-01-01

Recently, there has been much effort to find effective ingredients which can prevent or retard cutaneous skin aging after topical or systemic use. Here, we investigated the effects of the atomic hydrogen surrounded by water molecules, H(H2O)m, on acute UV-induced responses and as well as skin aging. Interestingly, we observed that H(H2O)m application to human skin prevented UV-induced erythema and DNA damage. And H(H2O)m significantly prevented UV-induced MMP-1, COX-2, IL-6 and IL-1β mRNA expressions in human skin in vivo. We found that H(H2O)m prevented UV-induced ROS generation and inhibited UV-induced MMP-1, COX-2 and IL-6 expressions, and UV-induced JNK and c-Jun phosphorylation in HaCaT cells. Next, we investigated the effects of H(H2O)m on intrinsically aged or photoaged skin of elderly subjects. In intrinsically aged skin, H(H2O)m application significantly reduced constitutive expressions of MMP-1, IL-6, and IL-1β mRNA. Additionally, H(H2O)m significantly increased procollagen mRNA and also decreased MMP-1 and IL-6 mRNA expressions in photoaged facial skin. These results demonstrated that local application of H(H2O)m may prevent UV-induced skin inflammation and can modulate intrinsic skin aging and photoaging processes. Therefore, we suggest that modifying the atmospheric gas environment within a room may be a new way to regulate skin functions or skin aging.

Atomic Hydrogen Surrounded by Water Molecules, H(H2O)m, Modulates Basal and UV-Induced Gene Expressions in Human Skin In Vivo

PubMed Central

Shin, Mi Hee; Park, Raeeun; Nojima, Hideo; Kim, Hyung-Chel; Kim, Yeon Kyung; Chung, Jin Ho

2013-01-01

Recently, there has been much effort to find effective ingredients which can prevent or retard cutaneous skin aging after topical or systemic use. Here, we investigated the effects of the atomic hydrogen surrounded by water molecules, H(H2O)m, on acute UV-induced responses and as well as skin aging. Interestingly, we observed that H(H2O)m application to human skin prevented UV-induced erythema and DNA damage. And H(H2O)m significantly prevented UV-induced MMP-1, COX-2, IL-6 and IL-1β mRNA expressions in human skin in vivo. We found that H(H2O)m prevented UV-induced ROS generation and inhibited UV-induced MMP-1, COX-2 and IL-6 expressions, and UV-induced JNK and c-Jun phosphorylation in HaCaT cells. Next, we investigated the effects of H(H2O)m on intrinsically aged or photoaged skin of elderly subjects. In intrinsically aged skin, H(H2O)m application significantly reduced constitutive expressions of MMP-1, IL-6, and IL-1β mRNA. Additionally, H(H2O)m significantly increased procollagen mRNA and also decreased MMP-1 and IL-6 mRNA expressions in photoaged facial skin. These results demonstrated that local application of H(H2O)m may prevent UV-induced skin inflammation and can modulate intrinsic skin aging and photoaging processes. Therefore, we suggest that modifying the atmospheric gas environment within a room may be a new way to regulate skin functions or skin aging. PMID:23637886

METHYL METHANESULFONATE-INDUCED GENE EXPRESSION CHANGES IN HUMAN SKIN FIBROBLASTS

EPA Science Inventory

METHYL METHANESULFONATE-INDUCED GENE EXPRESSION CHANGES IN HUMAN SKIN FIBROBLASTS. Geremy W. Knapp, Alan Tennant, and Russell D. Owen. Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U. S. Environmental Protection Agency, Re...

Ultraviolet Radiations: Skin Defense-Damage Mechanism.

PubMed

Mohania, Dheeraj; Chandel, Shikha; Kumar, Parveen; Verma, Vivek; Digvijay, Kumar; Tripathi, Deepika; Choudhury, Khushboo; Mitten, Sandeep Kumar; Shah, Dilip

2017-01-01

UV-radiations are the invisible part of light spectra having a wavelength between visible rays and X-rays. Based on wavelength, UV rays are subdivided into UV-A (320-400 nm), UV-B (280-320 nm) and UV-C (200-280 nm). Ultraviolet rays can have both harmful and beneficial effects. UV-C has the property of ionization thus acting as a strong mutagen, which can cause immune-mediated disease and cancer in adverse cases. Numbers of genetic factors have been identified in human involved in inducing skin cancer from UV-radiations. Certain heredity diseases have been found susceptible to UV-induced skin cancer. UV radiations activate the cutaneous immune system, which led to an inflammatory response by different mechanisms. The first line of defense mechanism against UV radiation is melanin (an epidermal pigment), and UV absorbing pigment of skin, which dissipate UV radiation as heat. Cell surface death receptor (e.g. Fas) of keratinocytes responds to UV-induced injury and elicits apoptosis to avoid malignant transformation. In addition to the formation of photo-dimers in the genome, UV also can induce mutation by generating ROS and nucleotides are highly susceptible to these free radical injuries. Melanocortin 1 receptor (MC1R) has been known to be implicated in different UV-induced damages such as pigmentation, adaptive tanning, and skin cancer. UV-B induces the formation of pre-vitamin D3 in the epidermal layer of skin. UV-induced tans act as a photoprotection by providing a sun protection factor (SPF) of 3-4 and epidermal hyperplasia. There is a need to prevent the harmful effects and harness the useful effects of UV radiations.

The Methoxyflavonoid Isosakuranetin Suppresses UV-B-Induced Matrix Metalloproteinase-1 Expression and Collagen Degradation Relevant for Skin Photoaging.

PubMed

Jung, Hana; Lee, Eunjoo H; Lee, Tae Hoon; Cho, Man-Ho

2016-09-01

Solar ultraviolet (UV) radiation is a main extrinsic factor for skin aging. Chronic exposure of the skin to UV radiation causes the induction of matrix metalloproteinases (MMPs), such as MMP-1, and consequently results in alterations of the extracellular matrix (ECM) and skin photoaging. Flavonoids are considered as potent anti-photoaging agents due to their UV-absorbing and antioxidant properties and inhibitory activity against UV-mediated MMP induction. To identify anti-photoaging agents, in the present study we examined the preventative effect of methoxyflavonoids, such as sakuranetin, isosakuranetin, homoeriodictyol, genkwanin, chrysoeriol and syringetin, on UV-B-induced skin photo-damage. Of the examined methoxyflavonoids, pretreatment with isosakuranetin strongly suppressed the UV-B-mediated induction of MMP-1 in human keratinocytes in a concentration-dependent manner. Isosakuranetin inhibited UV-B-induced phosphorylation of mitogen-activated protein kinase (MAPK) signaling components, ERK1/2, JNK1/2 and p38 proteins. This result suggests that the ERK1/2 kinase pathways likely contribute to the inhibitory effects of isosakuranetin on UV-induced MMP-1 production in human keratinocytes. Isosakuranetin also prevented UV-B-induced degradation of type-1 collagen in human dermal fibroblast cells. Taken together, our findings suggest that isosakuranetin has the potential for development as a protective agent for skin photoaging through the inhibition of UV-induced MMP-1 production and collagen degradation.

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

PubMed

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.

Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis.

PubMed

Sirerol, J Antoni; Feddi, Fatima; Mena, Salvador; Rodriguez, María L; Sirera, Paula; Aupí, Miguel; Pérez, Salvador; Asensi, Miguel; Ortega, Angel; Estrela, José M

2015-08-01

The aim of our study was to investigate in the SKH-1 hairless mouse model the effect of pterostilbene (Pter), a natural dimethoxy analog of resveratrol (Resv), against procarcinogenic ultraviolet B radiation (UVB)-induced skin damage. Pter prevented acute UVB (360 mJ/cm(2))-induced increase in skin fold, thickness, and redness, as well as photoaging-associated skin wrinkling and hyperplasia. Pter, but not Resv, effectively prevented chronic UVB (180 mJ/cm(2), three doses/week for 6 months)-induced skin carcinogenesis (90% of Pter-treated mice did not develop skin carcinomas, whereas a large number of tumors were observed in all controls). This anticarcinogenic effect was associated with (a) maintenance of skin antioxidant defenses (i.e., glutathione (GSH) levels, catalase, superoxide, and GSH peroxidase activities) close to control values (untreated mice) and (b) an inhibition of UVB-induced oxidative damage (using as biomarkers 8-hydroxy-2'-deoxyguanosine, protein carbonyls, and isoprostanes). The molecular mechanism underlying the photoprotective effect elicited by Pter was further evaluated using HaCaT immortalized human keratinocytes and was shown to involve potential modulation of the Nrf2-dependent antioxidant response. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of Akt enhances the chemopreventive effects of topical rapamycin in mouse skin

USGS Publications Warehouse

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

2016-01-01

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

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

PubMed Central

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

2016-01-01

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced non-melanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin, (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared to those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here we explored the use of topical rapamycin as a chemopreventive agent in the context of solar simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared to controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared to vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. PMID:26801880

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

PubMed

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

2016-03-01

The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC. ©2016 American Association for Cancer Research.

Keratinocyte p38δ loss inhibits Ras-induced tumor formation, while systemic p38δ loss enhances skin inflammation in the early phase of chemical carcinogenesis in mouse skin.

PubMed

Kiss, Alexi; Koppel, Aaron C; Anders, Joanna; Cataisson, Christophe; Yuspa, Stuart H; Blumenberg, Miroslav; Efimova, Tatiana

2016-05-01

p38δ expression and/or activity are increased in human cutaneous malignancies, including invasive squamous cell carcinoma (SCC) and head and neck SCC, but the role of p38δ in cutaneous carcinogenesis has not been well-defined. We have reported that mice with germline loss of p38δ exhibited a reduced susceptibility to skin tumor development compared with wild-type mice in the two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical skin carcinogenesis model. Here, we report that p38δ gene ablation inhibited the growth of tumors generated from v-ras(Ha) -transformed keratinocytes in skin orthografts to nude mice, indicating that keratinocyte-intrinsic p38δ is required for Ras-induced tumorigenesis. Gene expression profiling of v-ras(Ha) -transformed p38δ-null keratinocytes revealed transcriptional changes associated with cellular responses linked to tumor suppression, such as reduced proliferation and increased differentiation, cell adhesion, and cell communications. Notably, a short-term DMBA/TPA challenge, modeling the initial stages of chemical skin carcinogenesis treatment, elicited an enhanced inflammation in p38δ-null skin compared with skin of wild-type mice, as assessed by measuring the expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-17, and TNFα. Additionally, p38δ-null skin and p38δ-null keratinocytes exhibited increased p38α activation and signaling in response to acute inflammatory challenges, suggesting a role for p38α in stimulating the elevated inflammatory response in p38δ-null skin during the initial phases of the DMBA/TPA treatment compared with similarly treated p38δ(+/+) skin. Altogether, our results indicate that p38δ signaling regulates skin carcinogenesis not only by keratinocyte cell-autonomous mechanisms, but also by influencing the interaction between between the epithelial compartment of the developing skin tumor and its stromal microenvironment. © 2015 Wiley Periodicals, Inc.

Prevention of UV-induced skin damages by 11,14,17-eicosatrienoic acid in hairless mice in vivo.

PubMed

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

2010-06-01

Polyunsaturated fatty acids (PUFAs) are known to play important roles in various physiological and pathological processes. Recent studies have shown that some omega-3 (omega-3) PUFAs, such as eicosapentaenoic acid (EPA) and dodecahexaenoic acid (DHA), have protective effects on acute and chronic UV-induced changes. However, the effects of other omega-3 PUFAs including 11,14,17-eicosatrienoic acid (20:3) (ETA) on UV-induced skin damages are poorly understood. In this study, we investigated the cutaneous photoprotective effects of ETA in hairless mice in vivo. Female HR-1 hairless mice were topically treated with vehicle (ethanol:polyethylene glycol=30:70) only, 0.1% ETA, or 1% ETA once a day for 3 successive days after one time UV irradiation (200 mJ/cm(2)) on dorsal skins. Skin biopsy was carried out on the fourth day (72 hr after UV irradiation). We found that topical treatment with ETA attenuated UV-induced epidermal and dermal thickness and infiltration of inflammatory cells, and impairment of skin barrier function. In addition, ETA suppressed the expression of IL-1beta, COX-2, and MMP-13 induced by UV irradiation. Our results show that the topical application of ETA protects against UV-induced skin damage in hairless mice and suggest that ETA can be a potential agent for preventing and/or treating UV-induced inflammation and photoaging.

Are there mechanistic differences between ultraviolet and visible radiation induced skin pigmentation?

PubMed

Ramasubramaniam, Rajagopal; Roy, Arindam; Sharma, Bharati; Nagalakshmi, Surendra

2011-12-01

Most of the studies on sunlight-induced pigmentation of skin are mainly focused on ultraviolet (UV) radiation-induced pigmentation and ways to prevent it. Recent studies have shown that the visible component of sunlight can also cause significant skin pigmentation. In the current study, the extent of pigmentation induced by UV and visible regions of sunlight in subjects with Fitzpatrick skin type IV-V was measured and compared with pigmentation induced by total sunlight. The immediate pigment darkening (IPD) induced by the visible fraction of sunlight is not significantly different from that induced by the UV fraction. However, the persistent pigment darkening (PPD) induced by visible fraction of sunlight in significantly lower than that induced by the UV fraction. The dose responses of IPD induced by UV, visible light and total sunlight suggest that both UV and visible light interact with the same precursor although UV is 25 times more efficient in inducing pigmentation per J cm(-2) of irradiation compared to visible radiation. The measured diffused reflection spectra and decay kinetics of UV and visible radiation-induced pigmentation are very similar, indicating that the nature of the transient and persistent species involved in both the processes are also likely to be same.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

1986-05-29

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

AGE-RELATED GENE EXPRESSION CHANGES IN HUMAN SKIN FIBROBLASTS INDUCED BY MMS

EPA Science Inventory

Age-Related Gene Expression Changes In Human Skin Fibroblasts Induced By methyl methanesulfonate. Geremy W. Knapp, Alan H. Tennant, and Russell D. Owen. Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, U. S. Environmental Prote...

Endocrine actions of vitamin D in skin: Relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond.

PubMed

Reichrath, Jörg; Saternus, Roman; Vogt, Thomas

2017-09-15

The skin represents a pivotal organ for the human body's vitamin D endocrine system, being both the site of ultraviolet (UV)-B-induced vitamin D synthesis and a target tissue for the pluripotent effects of 1,25(OH) 2 D 3 and other biologically active vitamin D metabolites. As many other steroid hormones, 1,25(OH) 2 D 3 exerts its effects via two independent signal transduction pathways: the classical genomic and the non-genomic pathway. While non-genomic effects of 1,25(OH) 2 D 3 are in part exerted via effects on intracellular calcium, genomic effects are mediated by the vitamin D receptor (VDR). Recent findings convincingly support the concept of a new function of the VDR as a tumor suppressor in skin, with key components of the vitamin D endocrine system, including VDR, CYP24A1, CYP27A1, and CYP27B1 being strongly expressed in non-melanoma skin cancer (NMSC). It has now been shown that anti-tumor effects of VDR, that include some of its ligand-induced growth-regulatory effects, are at least in part mediated by interacting in a highly coordinated manner with the p53 family (p53/p63/p73) in response to a large number of alterations in cell homeostasis, including UV-induced DNA damage, a hallmark for skin photocarcinogenesis. Considering the relevance of the vitamin D endocrine system for carcinogenesis of skin cancer, it is not surprising that low 25(OH)D serum concentrations and genetic variants (SNPs) of the vitamin D endocrine system have been identified as potential risk factors for occurrence and prognosis of skin malignancies. In conclusion, an increasing body of evidence now convincingly supports the concept that the vitamin D endocrine system is of relevance for photocarcinogenesis and progression of NMSC and that its pharmacologic modulation by vitamin D, 1,25(OH) 2 D 3, and analogs represents a promising new strategy for prevention and/or treatment of these malignancies. Copyright © 2017 Elsevier B.V. All rights reserved.

Phloretin Inhibits Phorbol Ester–Induced Tumor Promotion and Expression of Cyclooxygenase-2 in Mouse Skin: Extracellular Signal-Regulated Kinase and Nuclear Factor-κB as Potential Targets

PubMed Central

Shin, Jun-Wan; Kundu, Joydeb Kumar

2012-01-01

Abstract The present study investigated the effect of phloretin [2′,4′,6′-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)–induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis. PMID:22181070

Phloretin inhibits phorbol ester-induced tumor promotion and expression of cyclooxygenase-2 in mouse skin: extracellular signal-regulated kinase and nuclear factor-κB as potential targets.

PubMed

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

2012-03-01

The present study investigated the effect of phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and explored the underlying molecular mechanisms. Topical application of phloretin significantly inhibited 7,12-dimethylbenz[a]anthracene-initiated and TPA-promoted mouse skin carcinogenesis. Pretreatment with phloretin on the dorsal skin of mice inhibited TPA-induced COX-2 expression in a dose-dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by phloretin, we examined its effect on TPA-induced activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor responsible for TPA-induced COX-2 expression in mouse skin. Topically applied phloretin decreased the TPA-induced DNA binding of NF-κB. In addition, phloretin inhibited the phosphorylation as well as the catalytic activity of extracellular signal-regulated kinase (ERK), which was previously found to activate NF-κB and induce COX-2 expression in TPA-treated mouse skin. Taken together, the inhibitory effects of phloretin on TPA-induced NF-κB activation and COX-2 expression through the modulation of ERK signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.

Topical or oral treatment of peach flower extract attenuates UV-induced epidermal thickening, matrix metalloproteinase-13 expression and pro-inflammatory cytokine production in hairless mice skin

PubMed Central

Yang, Jiwon; Shin, Chang-Yup; Chung, Jin Ho

2018-01-01

BACKGROUND/OBJECTIVES Ultraviolet radiation (UV) is a major cause of skin photoaging. Previous studies reported that ethanol extract (PET) of Prunus persica (L.) Batsch flowers (PPF, peach flowers) and its subfractions, particularly the ethylacetate (PEA) and n-butanol extracts (PBT), have potent antioxidant activity and attenuate the UV-induced matrix metalloproteinase (MMP) expression in human skin cells. In this study, we investigated the protective activity of PPF extract against UV-induced photoaging in a mouse model. MATERIALS/METHODS Hairless mice were treated with PET or a mixture of PEA and PBT either topically or orally along with UV irradiation. Histological changes and biochemical alterations of mouse skin were examined. Major phenolic compounds in PPF extract were analyzed using an ACQUITY UPLC system. RESULTS The overall effects of topical and oral treatments with PPF extract on the UV-induced skin responses exhibited similar patterns. In both experiments, the mixture of PEA and PBT significantly inhibited the UV-induced skin and epidermal thickening, while PET inhibited only the UV-induced epidermal thickening. Treatment of PET or the mixture of PEA and PBT significantly inhibited the UV-induced MMP-13 expression, but not typeⅠ collagen expression. Topical treatment of the mixture of PEA and PBT with UV irradiation significantly elevated catalase, superoxide dismutase (SOD) and glutathione-peroxidase (GPx) activities in the skin compared to those in the UV irradiated control group, while oral treatment of the mixture of PEA and PBT or PET elevated only catalase and SOD activities, but not GPx. Thirteen phytochemical compounds including 4-O-caffeoylquinic acid, cimicifugic acid E and B, quercetin-3-O-rhamnoside and kaempferol glycoside derivatives were identified in the PPF extract. CONCLUSIONS These results demonstrate that treatment with PET or the mixture of PEA and PBT, both topically or orally, attenuates UV-induced photoaging via the cooperative interactions of phenolic components having anti-oxidative and collagen-protective activities. PMID:29399294

N-(4-bromophenethyl) Caffeamide Inhibits Melanogenesis by Regulating AKT/Glycogen Synthase Kinase 3 Beta/Microphthalmia-associated Transcription Factor and Tyrosinase-related Protein 1/Tyrosinase.

PubMed

Kuo, Yueh-Hsiung; Chen, Chien-Chia; Lin, Ping; You, Ya-Jhen; Chiang, Hsiu-Mei

2015-01-01

Skin color is primarily produced by melanin, which is a crucial pigment that protects the skin from UV-induced damage and prevents carcinogenesis. However, accumulated melanin in the skin may cause hyperpigmentation and related disorders. Melanin synthesis comprises consecutive oxidative reactions, and tyrosinase is the enzyme that catalyzes the rate-limiting process of melanogenesis. In this study, tyrosinase-related protein 1 (TRP-1) and TRP-2 contributed to melanin formation. N-(4-bromophenethyl) caffeamide ((E)-N-(4-bromophenethyl)-3-(3,4-dihydroxyphenyl)acrylamide; K36H), a caffeic acid phenyl amide derivative, inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and tyrosinase activity in B16F0 cells. In addition, K36H reduced the protein expression of the phospho-cAMP response element binding protein (p-CREB), microphthalmia-associated transcription factor (MITF), tyrosinase, and TRP-1. Moreover, K36H promoted AKT and glycogen synthase kinase 3 beta (GSK3β) phosphorylation, thereby inhibiting MITF transcription activity. Thus, K36H attenuated α-MSH-induced cAMP pathways, contributing to hypopigmentation. The results of a safety assay revealed that K36H did not exhibit cytotoxicity or irritate the skin or eyes. According to these results, K36H may have the potential to be used as a whitening agent in the cosmetic and pharmaceutical industries.

Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV-VIS broadband radiation.

PubMed

Lee, Yuan-Hao; Wang, Exing; Kumar, Neeru; Glickman, Randolph D

2014-05-01

The signaling pathways via mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways can be modulated by naturally occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-κB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. UA-modulated apoptosis, following exposure to UV-VIS radiation (ultraviolet to visible light broadband radiation, hereafter abbreviated to UVR), is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. The cellular response to this phytochemical was characterized using western blot, flow cytometry, microscopy with reactive oxidative species probes MitoTracker and dihydroethidium, and membrane permeability assay. UA pretreatment potentiated cell cycle arrest and UVR-induced apoptosis selectively in SM cells while reducing photo-oxidative stress in the DNA of RPE cells presumably by antioxidant activity of UA. Mechanistically, the nuclear transportation of p65 and p53 was reduced by UA administration prior to UVR exposure while the levels of p65 and p53 nuclear transportation in SM cells were sustained at a substantially higher level. Finally, the mitochondrial functional assay showed that UVR induced the collapse of the mitochondrial membrane potential, and this effect was exacerbated by rapamycin or UA pretreatment in SM preferentially. These results were consistent with reduced proliferation observed in the clonogenic assay, indicating that UA treatment enhanced the phototoxicity of UVR, by modulating the activation of p53 and NF-κB and initiating a mitogenic response to optical radiation that triggered mitochondria-dependent apoptosis, particularly in skin melanoma cells. The study indicates that this compound has multiple actions with the potential for protecting normal cells while sensitizing skin melanoma cells to UV irradiation.

Caffeic Acid Inhibits Chronic UVB-Induced Cellular Proliferation Through JAK-STAT3 Signaling in Mouse Skin.

PubMed

Agilan, Balupillai; Rajendra Prasad, N; Kanimozhi, Govindasamy; Karthikeyan, Ramasamy; Ganesan, Muthusamy; Mohana, Shanmugam; Velmurugan, Devadasan; Ananthakrishnan, Dhanapalan

2016-05-01

Signal transducers and activators of transcription 3 (STAT3) play a critical role in inflammation, proliferation and carcinogenesis. Inhibition of JAK-STAT3 signaling is proved to be a novel target for prevention of UVB-induced skin carcinogenesis. In this study, chronic UVB irradiation (180 mJ cm(-2) ; weekly thrice for 30 weeks) induces the expression of IL-10 and JAK1 that eventually activates the STAT3 which leads to the transcription of proliferative and antiapoptotic markers such as PCNA, Cyclin-D1, Bcl2 and Bcl-xl, respectively. Caffeic acid (CA) inhibits JAK-STAT3 signaling, thereby induces apoptotic cell death by upregulating Bax, Cytochrome-C, Caspase-9 and Caspase-3 expression in mouse skin. Furthermore, TSP-1 is an antiangiogeneic protein, which is involved in the inhibition of angiogenesis and proliferation. Chronic UVB exposure decreased the expression of TSP-1 and pretreatment with CA prevented the UVB-induced loss of TSP-1 in UVB-irradiated mouse skin. Thus, CA offers protection against UVB-induced photocarcinogenesis probably through modulating the JAK-STAT3 in the mouse skin. © 2016 The American Society of Photobiology.

Polyhydroxylated fatty alcohols derived from avocado suppress inflammatory response and provide non-sunscreen protection against UV-induced damage in skin cells.

PubMed

Rosenblat, Gennady; Meretski, Shai; Segal, Joseph; Tarshis, Mark; Schroeder, Avi; Zanin-Zhorov, Alexandra; Lion, Gilead; Ingber, Arieh; Hochberg, Malka

2011-05-01

Exposing skin to ultraviolet (UV) radiation contributes to photoaging and to the development of skin cancer by DNA lesions and triggering inflammatory and other harmful cellular cascades. The present study tested the ability of unique lipid molecules, polyhydroxylated fatty alcohols (PFA), extracted from avocado, to reduce UVB-induced damage and inflammation in skin. Introducing PFA to keratinocytes prior to their exposure to UVB exerted a protective effect, increasing cell viability, decreasing the secretion of IL-6 and PGE(2), and enhancing DNA repair. In human skin explants, treating with PFA reduced significantly UV-induced cellular damage. These results support the idea that PFA can play an important role as a photo-protective agent in UV-induced skin damage.

UV radiation induces CXCL5 expression in human skin.

PubMed

Reichert, Olga; Kolbe, Ludger; Terstegen, Lara; Staeb, Franz; Wenck, Horst; Schmelz, Martin; Genth, Harald; Kaever, Volkhard; Roggenkamp, Dennis; Neufang, Gitta

2015-04-01

CXCL5 has recently been identified as a mediator of UVB-induced pain in rodents. To compare and to extend previous knowledge of cutaneous CXCL5 regulation, we performed a comprehensive study on the effects of UV radiation on CXCL5 regulation in human skin. Our results show a dose-dependent increase in CXCL5 protein in human skin after UV radiation. CXCL5 can be released by different cell types in the skin. We presumed that, in addition to immune cells, non-immune skin cells also contribute to UV-induced increase in CXCL5 protein. Analysis of monocultured dermal fibroblasts and keratinocytes revealed that only fibroblasts but not keratinocytes displayed up regulated CXCL5 levels after UV stimulation. Whereas UV treatment of human skin equivalents, induced epidermal CXCL5 mRNA and protein expression. Up regulation of epidermal CXCL5 was independent of keratinocyte differentiation and keratinocyte-keratinocyte interactions in epidermal layers. Our findings provide first evidence on the release of CXCL5 in UV-radiated human skin and the essential role of fibroblast-keratinocyte interaction in the regulation of epidermal CXCL5. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans.

PubMed

Knatko, Elena V; Ibbotson, Sally H; Zhang, Ying; Higgins, Maureen; Fahey, Jed W; Talalay, Paul; Dawe, Robert S; Ferguson, James; Huang, Jeffrey T-J; Clarke, Rosemary; Zheng, Suqing; Saito, Akira; Kalra, Sukirti; Benedict, Andrea L; Honda, Tadashi; Proby, Charlotte M; Dinkova-Kostova, Albena T

2015-06-01

The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro-inflammatory factors IL6 and IL1β, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. ©2015 American Association for Cancer Research.

Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans

PubMed Central

Knatko, Elena V.; Ibbotson, Sally H.; Zhang, Ying; Higgins, Maureen; Fahey, Jed W.; Talalay, Paul; Dawe, Robert S.; Ferguson, James; Huang, Jeffrey T.-J.; Clarke, Rosemary; Zheng, Suqing; Saito, Akira; Kalra, Sukirti; Benedict, Andrea L.; Honda, Tadashi; Proby, Charlotte M.; Dinkova-Kostova, Albena T.

2015-01-01

The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity and burden of solar-simulated UV radiation-mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated, are lower than those that arise in their wild-type counterparts. Pharmacological Nrf2 activation by topical bi-weekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacological Nrf2 activation lowers the expression of the pro-inflammatory factors interleukin (IL)-6 and IL-1β, and cyclooxygenase (COX)-2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane, reduced the degree of solar-simulated UV radiation-induced skin erythema, a quantifiable surrogate end-point for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen, and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. PMID:25804610

Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation

PubMed Central

Zhan, Janis Ya-Xian; Wang, Xiu-Fen; Liu, Yu-Hong; Zhang, Zhen-Biao; Wang, Lan; Chen, Jian-Nan; Huang, Song; Zeng, Hui-Fang; Lai, Xiao-Ping

2016-01-01

Andrographolide sodium bisulfate (ASB), a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV) irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent. PMID:26903706

Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation.

PubMed

Zhan, Janis Ya-Xian; Wang, Xiu-Fen; Liu, Yu-Hong; Zhang, Zhen-Biao; Wang, Lan; Chen, Jian-Nan; Huang, Song; Zeng, Hui-Fang; Lai, Xiao-Ping

2016-01-01

Andrographolide sodium bisulfate (ASB), a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV) irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent.

Chemomodulatory Potential of Flaxseed Oil Against DMBA/Croton Oil-Induced Skin Carcinogenesis in Mice.

PubMed

Sharma, Jyoti; Singh, Ritu; Goyal, P K

2016-09-01

The present study was conducted to evaluate the potential of flaxseed oil to prevent chemically induced skin cancer in mice. Cancer was induced on 2-stage skin carcinogenesis model by single topical application of 7,12 dimethylbenz [a]anthracene (DMBA), as, initiator, and two weeks later it was promoted by croton oil treatment thrice a week on the dorsal surface of mice for 16 weeks. Flaxseed oil (FSO; 100µL/animal/d) was orally administered 1 week before and 1 week after DMBA application (Peri-initiation stage). The animals of the FSO-administered group showed a significant reduction in tumor incidence (76.67%), cumulative number of tumors (37), tumor yield (3.7), and tumor burden (4.81) when compared with the carcinogen-treated control animals. Biochemical parameters in skin and liver tissue such as LPO and phase I enzymes were significantly (P < .01) reduced in the FSO-treated experimental group, whereas the phase II enzymes (GST, DT-diaphorase) and antioxidant parameters (GSH, GPx, SOD, catalase, and vitamin C) exhibited a significant (P < .01) elevation when compared with the animals of the carcinogen-treated control group. Histopathological alterations in the carcinogen-treated control animals were also observed in the form of epidermal hyperplasia, keratinized pearl formation, and acanthosis in skin and tumors, whereas these were found to be reduced after FSO administration. The results of the present study demonstrate that the oral administration of FSO has the potential to modulate the levels of LPO, antioxidants, and detoxification enzymes in the DMBA-croton oil-induced skin carcinogenesis in mice. © The Author(s) 2015.

Purification and growth of melanocortin 1 receptor (Mc1r)-defective primary murine melanocytes is dependent on stem cell factor from keratinocyte-conditioned media

PubMed Central

Scott, Timothy L.; Wakamatsu, Kazumasa; Ito, Shosuke; D’Orazio, John A.

2015-01-01

Summary The melanocortin 1 receptor (MC1R) is a transmembrane Gs-coupled surface protein found on melanocytes that binds melanocyte stimulating hormone (MSH) and mediates activation of adenylyl cyclase and generation of the second messenger cAMP. MC1R regulates growth and differentiation of melanocytes and protects against carcinogenesis. Persons with loss-of-function polymorphisms of MC1R tend to be UV-sensitive (fair-skinned and with a poor tanning response) and are at high risk for melanoma. Mechanistic studies of the role of MC1R in melanocytic UV responses, however, have been hindered in part because Mc1r-defective primary murine melanocytes have been difficult to culture in vitro. Until now, effective growth of murine melanocytes has depended on cAMP stimulation with adenylyl cyclase activating or phosphodiesterase inhibiting agents. However, rescuing cAMP in the setting of defective MC1R signaling would be expected to confound experiments directly testing MC1R function on melanocytic UV responses. Here we report a novel method of culturing primary murine melanocytes in the absence of pharmacologic cAMP stimulation by incorporating conditioned supernatants containing stem cell factor (SCF) derived from primary keratinocytes. Importantly, this method seems to permit similar pigment expression by cultured melanocytes as that found in the skin of their parental murine strains. This novel approach will allow mechanistic investigation into MC1R’s role in protection against UV-mediated carcinogenesis and determination of the role of melanin pigment subtypes on UV-mediated melanocyte responses. PMID:19633898

Studies on glyphosate-induced carcinogenicity in mouse skin: a proteomic approach.

PubMed

George, Jasmine; Prasad, Sahdeo; Mahmood, Zafar; Shukla, Yogeshwer

2010-03-10

Glyphosate is a widely used broad spectrum herbicide, reported to induce various toxic effects in non-target species, but its carcinogenic potential is still unknown. Here we showed the carcinogenic effects of glyphosate using 2-stage mouse skin carcinogenesis model and proteomic analysis. Carcinogenicity study revealed that glyphosate has tumor promoting activity. Proteomic analysis using 2-dimensional gel electrophoresis and mass spectrometry showed that 22 spots were differentially expressed (>2 fold) on glyphosate, 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) application over untreated control. Among them, 9 proteins (translation elongation factor eEF-1 alpha chain, carbonic anhydrase III, annexin II, calcyclin, fab fragment anti-VEGF antibody, peroxiredoxin-2, superoxide dismutase [Cu-Zn], stefin A3, and calgranulin-B) were common and showed similar expression pattern in glyphosate and TPA-treated mouse skin. These proteins are known to be involved in several key processes like apoptosis and growth-inhibition, anti-oxidant responses, etc. The up-regulation of calcyclin, calgranulin-B and down-regulation of superoxide dismutase [Cu-Zn] was further confirmed by immunoblotting, indicating that these proteins can be good candidate biomarkers for skin carcinogenesis induced by glyphosate. Altogether, these results suggested that glyphosate has tumor promoting potential in skin carcinogenesis and its mechanism seems to be similar to TPA. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis.

PubMed

García-Nieto, Pablo E; Schwartz, Erin K; King, Devin A; Paulsen, Jonas; Collas, Philippe; Herrera, Rafael E; Morrison, Ashby J

2017-10-02

The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer. © 2017 The Authors.

Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms.

PubMed

Nichols, Joi A; Katiyar, Santosh K

2010-03-01

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation in various skin diseases including, premature aging of the skin and melanoma and non-melanoma skin cancers. Chronic UV radiation exposure-induced skin diseases or skin disorders are caused by the excessive induction of inflammation, oxidative stress and DNA damage, etc. The use of chemopreventive agents, such as plant polyphenols, to inhibit these events in UV-exposed skin is gaining attention. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of these harmful events in the UV-exposed skin. A wide variety of polyphenols or phytochemicals, most of which are dietary supplements, have been reported to possess substantial skin photoprotective effects. This review article summarizes the photoprotective effects of some selected polyphenols, such as green tea polyphenols, grape seed proanthocyanidins, resveratrol, silymarin and genistein, on UV-induced skin inflammation, oxidative stress and DNA damage, etc., with a focus on mechanisms underlying the photoprotective effects of these polyphenols. The laboratory studies conducted in animal models suggest that these polyphenols have the ability to protect the skin from the adverse effects of UV radiation, including the risk of skin cancers. It is suggested that polyphenols may favorably supplement sunscreens protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and DNA damage.

Expression profile of microRNA-146a along HPV-induced multistep carcinogenesis: a study in HPV16 transgenic mice.

PubMed

Araújo, Rita; Santos, Joana M O; Fernandes, Mara; Dias, Francisca; Sousa, Hugo; Ribeiro, Joana; Bastos, Margarida M S M; Oliveira, Paula A; Carmo, Diogo; Casaca, Fátima; Silva, Sandra; Medeiros, Rui; Gil da Costa, Rui M

2018-02-01

Persistent human papillomavirus (HPV) infection is associated with the development of certain types of cancer and the dysregulation of microRNAs has been implicated in HPV-associated carcinogenesis. This is the case of microRNA-146a (miR-146a), which is thought to regulate tumor-associated inflammation. We sought to investigate the expression levels of miR-146a during HPV16-mediated carcinogenesis using skin samples from K14-HPV16 transgenic mice which develop the consecutive phases of the carcinogenesis process. Female transgenic (HPV +/- ) and wild-type (HPV -/- ) mice were sacrificed at 24-26 weeks-old or 28-30 weeks-old. Chest and ear skin samples from HPV +/- and HPV -/- mice were histologically classified and used for microRNA extraction and quantification by qPCR. Chest skin samples from 24 to 26 weeks-old HPV +/- mice presented diffuse epidermal hyperplasia and only 22.5% showed multifocal dysplasia, while at 28-30 weeks-old all (100.0%) HPV +/- animals showed epidermal dysplasia. All HPV +/- ear skin samples showed carcinoma in situ (CIS). MiR-146a expression levels were higher in HPV +/- compared to HPV -/- mice (p = 0.006). There was also an increase in miR-146a expression in dysplastic skin lesions compared with hyperplasic lesions (p = 0.011). Samples showing CIS had a significant decrease in miR-146a expression when compared to samples showing epidermal hyperplasia (p = 0.018) and epidermal dysplasia (p = 0.009). These results suggest that HPV16 induces the overexpression of miR-146a in the initial stages of carcinogenesis (hyperplasia and dysplasia), whereas decreases its expression at later stages (CIS). Taken together, these data implicate and suggest different roles of miR-146a in HPV-mediated carcinogenesis.

Regulation of Human Skin Pigmentation in situ by Repetitive UV Exposure – Molecular Characterization of Responses to UVA and/or UVB

PubMed Central

Choi, Wonseon; Miyamura, Yoshinori; Wolber, Rainer; Smuda, Christoph; Reinhold, William; Liu, Hongfang; Kolbe, Ludger; Hearing, Vincent J.

2012-01-01

Ultraviolet (UV) radiation is a major environmental factor that affects pigmentation in human skin and can eventually result in various types of UV-induced skin cancers. The effects of various wavelengths of UV on melanocytes and other types of skin cells in culture have been studied but little is known about gene expression patterns in situ following in situe exposure of human skin to different types of UV (UVA and/or UVB). Paracrine factors expressed by keratinocytes and/or fibroblasts that affect skin pigmentation might be regulated differently by UV, as might their corresponding receptors expressed on melanocytes. To test the hypothesis that different mechanisms are involved in the pigmentary responses of the skin to different types of UV, we used immunohistochemical and whole human genome microarray analyses to characterize human skin in situ to examine how melanocyte-specific proteins and paracrine melanogenic factors are regulated by repetitive exposure to different types of UV compared with unexposed skin as a control. The results show that gene expression patterns induced by UVA or UVB are distinct, UVB eliciting dramatic increases in a large number of genes involved in pigmentation as well as in other cellular functions, while UVA had little or no effect on those. The expression patterns characterize the distinct responses of the skin to UVA or UVB, and identify several potential previously unidentified factors involved in UV-induced responses of human skin. PMID:20147966

Dicer Cooperates with p53 to Suppress DNA Damage and Skin Carcinogenesis in Mice

PubMed Central

Lyle, Stephen; Hoover, Kathleen; Colpan, Cansu; Zhu, Zhiqing; Matijasevic, Zdenka; Jones, Stephen N.

2014-01-01

Dicer is required for the maturation of microRNA, and loss of Dicer and miRNA processing has been found to alter numerous biological events during embryogenesis, including the development of mammalian skin and hair. We have previously examined the role of miRNA biogenesis in mouse embryonic fibroblasts and found that deletion of Dicer induces cell senescence regulated, in part, by the p53 tumor suppressor. Although Dicer and miRNA molecules are thought to have either oncogenic or tumor suppressing roles in various types of cancer, a role for Dicer and miRNAs in skin carcinogenesis has not been established. Here we show that perinatal ablation of Dicer in the skin of mice leads to loss of fur in adult mice, increased epidermal cell proliferation and apoptosis, and the accumulation of widespread DNA damage in epidermal cells. Co-ablation of Dicer and p53 did not alter the timing or extent of fur loss, but greatly reduced survival of Dicer-skin ablated mice, as these mice developed multiple and highly aggressive skin carcinomas. Our results describe a new mouse model for spontaneous basal and squamous cell tumorigenesis. Furthermore, our findings reveal that loss of Dicer in the epidermis induces extensive DNA damage, activation of the DNA damage response and p53-dependent apoptosis, and that Dicer and p53 cooperate to suppress mammalian skin carcinogenesis. PMID:24979267

Lipoxin A4 inhibits UV radiation-induced skin inflammation and oxidative stress in mice.

PubMed

Martinez, R M; Fattori, V; Saito, P; Melo, C B P; Borghi, S M; Pinto, I C; Bussmann, A J C; Baracat, M M; Georgetti, S R; Verri, W A; Casagrande, R

2018-04-27

Lipoxin A4 (LXA 4 ) is a metabolic product of arachidonic acid. Despite potent anti-inflammatory and pro-resolution activities, it remains to be determined if LXA 4 has effect on ultraviolet (UV) radiation-induced skin inflammation. To investigate the effects of systemic administration with LXA 4 on UV radiation-induced inflammation and oxidative damage in the skin of mice. Varied parameters of inflammation and oxidative stress in the skin of mice were evaluated after UV radiation (4.14 J/cm 2 ). Pretreatment with LXA 4 significantly inhibited UV radiation-induced skin edema and myeloperoxidase activity. LXA 4 efficacy was enhanced by increasing the time of pre-treatment to up to 72 h. LXA 4 reduced UV radiation-induced skin edema, neutrophil recruitment (myeloperoxidase activity and LysM-eGFP + cells), MMP-9 activity, deposition of collagen fibers, epidermal thickness, sunburn cell counts, and production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-33). Depending on the time point, LXA 4 increased the levels of anti-inflammatory cytokines (TGF-β and IL-10). LXA 4 significantly attenuated UV radiation-induced oxidative damage returning the oxidative status to baseline levels in parameters such as ferric reducing ability, scavenging of free radicals, GSH levels, catalase activity and superoxide anion production. LXA 4 also reduced UV radiation-induced gp91 phox [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) subunit] mRNA expression and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target enzyme nicotinamide adenine dinucleotide (phosphate) quinone oxidoreductase (Nqo1) mRNA expression. LXA 4 inhibited UV radiation-induced skin inflammation by diminishing pro-inflammatory cytokine production and oxidative stress as well as inducing anti-inflammatory cytokines and Nrf2. Copyright © 2018. Published by Elsevier B.V.

Identification of a novel PPARβ/δ/miR-21-3p axis in UV-induced skin inflammation.

PubMed

Degueurce, Gwendoline; D'Errico, Ilenia; Pich, Christine; Ibberson, Mark; Schütz, Frédéric; Montagner, Alexandra; Sgandurra, Marie; Mury, Lionel; Jafari, Paris; Boda, Akash; Meunier, Julien; Rezzonico, Roger; Brembilla, Nicolò Costantino; Hohl, Daniel; Kolios, Antonios; Hofbauer, Günther; Xenarios, Ioannis; Michalik, Liliane

2016-08-01

Although excessive exposure to UV is widely recognized as a major factor leading to skin perturbations and cancer, the complex mechanisms underlying inflammatory skin disorders resulting from UV exposure remain incompletely characterized. The nuclear hormone receptor PPARβ/δ is known to control mouse cutaneous repair and UV-induced skin cancer development. Here, we describe a novel PPARβ/δ-dependent molecular cascade involving TGFβ1 and miR-21-3p, which is activated in the epidermis in response to UV exposure. We establish that the passenger miRNA miR-21-3p, that we identify as a novel UV-induced miRNA in the epidermis, plays a pro-inflammatory function in keratinocytes and that its high level of expression in human skin is associated with psoriasis and squamous cell carcinomas. Finally, we provide evidence that inhibition of miR-21-3p reduces UV-induced cutaneous inflammation in ex vivo human skin biopsies, thereby underlining the clinical relevance of miRNA-based topical therapies for cutaneous disorders. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

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

PubMed

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.

Progression of Mouse Skin Carcinogenesis Is Associated with Increased Erα Levels and Is Repressed by a Dominant Negative Form of Erα

PubMed Central

Michalopoulos, Ioannis; Sideridou, Maria; Tsimaratou, Katerina; Christodoulou, Ioannis; Pyrillou, Katerina; Gorgoulis, Vassilis; Vlahopoulos, Spiros; Zoumpourlis, Vassilis

2012-01-01

Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα. PMID:22870269

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis.

PubMed

Rigby, Cynthia M; Roy, Srirupa; Deep, Gagan; Guillermo-Lagae, Ruth; Jain, Anil K; Dhar, Deepanshi; Orlicky, David J; Agarwal, Chapla; Agarwal, Rajesh

2017-01-01

Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53 +/- ) and p53 knockout (p53 -/- ) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53 +/+ mice, p53 +/- mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53 +/+ mice but silibinin' protective efficacy was significantly compromised in p53 +/- mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53 -/- mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53 +/+ mice while its efficacy was partially compromised in p53 -/- mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis

PubMed Central

Rigby, Cynthia M.; Roy, Srirupa; Deep, Gagan; Guillermo-Lagae, Ruth; Jain, Anil K.; Dhar, Deepanshi; Orlicky, David J.; Agarwal, Chapla; Agarwal, Rajesh

2017-01-01

Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53+/−) and p53 knockout (p53−/−) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53+/+ mice, p53+/− mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53+/+ mice but silibinin’ protective efficacy was significantly compromised in p53+/− mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53−/− mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53+/+ mice while its efficacy was partially compromised in p53−/− mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation. PMID:27729375

1α,25(OH)2-dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the β-catenin pathway.

PubMed

Jiang, Yan J; Teichert, Arnaud E; Fong, Frankie; Oda, Yuko; Bikle, Daniel D

2013-07-01

Ultra violet (UV) irradiation, in particular UVB, is the single most important carcinogen for skin tumor formation. UVB induces genetic mutations and immune suppression, which lead to abnormal cell proliferation and eventually tumor formation. Previously studies from our group and others demonstrated that both global and epidermal specific VDR knock out mice are predisposed to either chemical (DMBA)- or long-term UVB-induced skin tumor formation, paralleled by an increase in β-catenin signaling. Using primary cultured human keratinocytes, we further demonstrated that 1,25(OH)2-dihydroxyvitamin D3 (1,25(OH)2D3) suppresses cyclin D1 and Gli1 which are regulated by β-catenin/TCF signaling and have a critical role in epidermal carcinogenesis. Blockage of VDR by siRNA resulted in hyperproliferation of keratinocytes, and increased expression of cyclin D1 and Gli1. In addition, we also showed that 1,25(OH)2D3/VDR directly regulates transcriptional activity of β-catenin/TCF signaling using the -catenin reporter TopGlow. Using K14 driven tamoxifen-induced cre recombinase to delete both VDR and β-catenin in keratinocytes of mice following the first hair follicle cycle, we found that ablation of epidermal specific β-catenin cannot rescue VDR null mice from UVB-induced skin tumor formation. Further study using VDR or β-catenin single null mice is necessary to compare with the data from double null mice. This article is part of a Special Issue entitled 'Vitamin D Workshop'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protective effect of red orange extract supplementation against UV-induced skin damages: photoaging and solar lentigines.

PubMed

Puglia, Carmelo; Offerta, Alessia; Saija, Antonella; Trombetta, Domenico; Venera, Cardile

2014-06-01

Exposure of the skin to solar ultraviolet (UV) radiations causes important oxidative damages that result in clinical and hystopathological changes, contributing to premature skin aging. Hyperpigmented lesions, also known as age spots, are one of the most visible alterations in skin photoaging. Skin is naturally equipped with antioxidant systems against UV-induced ROS generation; however, these antioxidant defenses are not completely efficient during exposure to sunlight. Oral antioxidants are able to counteract the harmful effects of UV radiation and to strengthen the physiological skin antioxidant defenses. The present study was performed to evaluate the in vivo skin photo-protecting and anti-aging effects of a red orange (Citrus sinensis varieties Moro, Tarocco and Sanguinello) extract supplementation. Previous studies showed that red orange extracts possess strong in vitro free radical scavenging/antioxidant activity and photo-protective effects on human skin. The photo-protective effects of red orange extract intake against UV-induced skin erythema and melanin production in solar lentigo was evaluated on healthy volunteers by an objective instrumental method (reflectance spectrophotometry). Data obtained from in vivo studies showed that supplementation of red orange extract (100 mg/daily) for 15 days brought a significant reduction in the UV-induced skin erythema degree. Moreover, skin age spots pigmentation (melanin content) decreased from 27% to 7% when subjects were exposed to solar lamp during red orange extract supplementation. Red orange extract intake can strengthen physiological antioxidant skin defenses, protecting skin from the damaging processes involved in photo-aging and leading to an improvement in skin appearance and pigmentation. © 2014 Wiley Periodicals, Inc.

2016 Arte Poster Competition First Place Winner: Circadian Rhythm and UV-Induced Skin Damage: An In Vivo Study.

PubMed

Guan, Linna; Suggs, Amanda; Ahsanuddin, Sayeeda; Tarrillion, Madeline; Selph, Jacqueline; Lam, Minh; Baron, Elma

2016-09-01

Exposure of the skin to ultraviolet (UV) irradiation causes many detrimental effects through mechanisms related to oxidative stress and DNA damage. Excessive oxidative stress can cause apoptosis and cellular dysfunction of epidermal cells leading to cellular senescence and connective tissue degradation. Direct and indirect damage to DNA predisposes the skin to cancer formation. Chronic UV exposure also leads to skin aging manifested as wrinkling, loss of skin tone, and decreased resilience. Fortunately, human skin has several natural mechanisms for combating UV-induced damage. The mechanisms operate on a diurnal rhythm, a cycle that repeats approximately every 24 hours. It is known that the circadian rhythm is involved in many skin physiologic processes, including water regulation and epidermal stem cell function. This study evaluated whether UV damage and the skin's natural mechanisms of inflammation and repair are also affected by circadian rhythm. We looked at UV-induced erythema on seven human subjects irradiated with simulated solar radiation in the morning (at 08:00 h) versus in the afternoon (at 16:00 h). Our data suggest that the same dose of UV radiation induces significantly more inflammation in the morning than in the afternoon. Changes in protein expression relevant to DNA damage, such as xeroderma pigmentosum, complementation group A (XPA), and cyclobutane pyrimidine dimers (CPD) from skin biopsies correlated with our clinical results. Both XPA and CPD levels were higher after the morning UV exposure compared with the afternoon exposure.

J Drugs Dermatol. 2016;15(9):1124-1130.

Sunlight damage to cellular DNA: Focus on oxidatively generated lesions.

PubMed

Schuch, André Passaglia; Moreno, Natália Cestari; Schuch, Natielen Jacques; Menck, Carlos Frederico Martins; Garcia, Camila Carrião Machado

2017-06-01

The routine and often unavoidable exposure to solar ultraviolet (UV) radiation makes it one of the most significant environmental DNA-damaging agents to which humans are exposed. Sunlight, specifically UVB and UVA, triggers various types of DNA damage. Although sunlight, mainly UVB, is necessary for the production of vitamin D, which is necessary for human health, DNA damage may have several deleterious consequences, such as cell death, mutagenesis, photoaging and cancer. UVA and UVB photons can be directly absorbed not only by DNA, which results in lesions, but also by the chromophores that are present in skin cells. This process leads to the formation of reactive oxygen species, which may indirectly cause DNA damage. Despite many decades of investigation, the discrimination among the consequences of these different types of lesions is not clear. However, human cells have complex systems to avoid the deleterious effects of the reactive species produced by sunlight. These systems include antioxidants, that protect DNA, and mechanisms of DNA damage repair and tolerance. Genetic defects in these mechanisms that have clear harmful effects in the exposed skin are found in several human syndromes. The best known of these is xeroderma pigmentosum (XP), whose patients are defective in the nucleotide excision repair (NER) and translesion synthesis (TLS) pathways. These patients are mainly affected due to UV-induced pyrimidine dimers, but there is growing evidence that XP cells are also defective in the protection against other types of lesions, including oxidized DNA bases. This raises a question regarding the relative roles of the various forms of sunlight-induced DNA damage on skin carcinogenesis and photoaging. Therefore, knowledge of what occurs in XP patients may still bring important contributions to the understanding of the biological impact of sunlight-induced deleterious effects on the skin cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Reverse Engineering Applied to Red Human Hair Pheomelanin Reveals Redox-Buffering as a Pro-Oxidant Mechanism

PubMed Central

Kim, Eunkyoung; Panzella, Lucia; Micillo, Raffaella; Bentley, William E.; Napolitano, Alessandra; Payne, Gregory F.

2015-01-01

Pheomelanin has been implicated in the increased susceptibility to UV-induced melanoma for people with light skin and red hair. Recent studies identified a UV-independent pathway to melanoma carcinogenesis and implicated pheomelanin’s pro-oxidant properties that act through the generation of reactive oxygen species and/or the depletion of cellular antioxidants. Here, we applied an electrochemically-based reverse engineering methodology to compare the redox properties of human hair pheomelanin with model synthetic pigments and natural eumelanin. This methodology exposes the insoluble melanin samples to complex potential (voltage) inputs and measures output response characteristics to assess redox activities. The results demonstrate that both eumelanin and pheomelanin are redox-active, they can rapidly (sec-min) and repeatedly redox-cycle between oxidized and reduced states, and pheomelanin possesses a more oxidative redox potential. This study suggests that pheomelanin’s redox-based pro-oxidant activity may contribute to sustaining a chronic oxidative stress condition through a redox-buffering mechanism. PMID:26669666

Reverse Engineering Applied to Red Human Hair Pheomelanin Reveals Redox-Buffering as a Pro-Oxidant Mechanism.

PubMed

Kim, Eunkyoung; Panzella, Lucia; Micillo, Raffaella; Bentley, William E; Napolitano, Alessandra; Payne, Gregory F

2015-12-16

Pheomelanin has been implicated in the increased susceptibility to UV-induced melanoma for people with light skin and red hair. Recent studies identified a UV-independent pathway to melanoma carcinogenesis and implicated pheomelanin's pro-oxidant properties that act through the generation of reactive oxygen species and/or the depletion of cellular antioxidants. Here, we applied an electrochemically-based reverse engineering methodology to compare the redox properties of human hair pheomelanin with model synthetic pigments and natural eumelanin. This methodology exposes the insoluble melanin samples to complex potential (voltage) inputs and measures output response characteristics to assess redox activities. The results demonstrate that both eumelanin and pheomelanin are redox-active, they can rapidly (sec-min) and repeatedly redox-cycle between oxidized and reduced states, and pheomelanin possesses a more oxidative redox potential. This study suggests that pheomelanin's redox-based pro-oxidant activity may contribute to sustaining a chronic oxidative stress condition through a redox-buffering mechanism.

Perilla frutescens leaves extract ameliorates ultraviolet radiation-induced extracellular matrix damage in human dermal fibroblasts and hairless mice skin.

PubMed

Bae, Jung-Soo; Han, Mira; Shin, Hee Soon; Kim, Min-Kyoung; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-01-04

Perilla frutescens (L.) Britt. (Lamiaceae) is a traditional herb that is consumed in East Asian countries as a traditional medicine. This traditional herb has been documented for centuries to treat various diseases such as depression, allergies, inflammation and asthma. However, the effect of Perilla frutescens on skin has not been characterized well. The present study aimed to investigate the effect of Perilla frutescens leaves extract (PLE) on ultraviolet radiation-induced extracellular matrix damage in human dermal fibroblasts and hairless mice skin. Human dermal fibroblasts and Skh-1 hairless mice were irradiated with UV and treated with PLE. Protein and mRNA levels of various target molecules were analyzed by western blotting and quantitative RT-PCR, respectively. Histological changes of mouse skin were analyzed by H&E staining. To elucidate underlying mechanism of PLE, activator protein-1 (AP-1) DNA binding assay and the measurement of reactive oxygen species (ROS) were performed. PLE significantly inhibited basal and UV-induced MMP-1 and MMP-3 expression dose-dependently, and also decreased UV-induced phosphorylation of extracellular signal-regulated kinases and c-Jun N-terminal kinases. This inhibitory effects of PLE on MMP-1 and MMP-3 were mediated by reduction of ROS generation and AP-1 DNA binding activity induced by UV. Furthermore, PLE promoted type I procollagen production irrespective of UV irradiation. In the UV-irradiated animal model, PLE significantly reduced epidermal skin thickness and MMP-13 expression induced by UV. Our results demonstrate that PLE has the protective effect against UV-induced dermal matrix damage. Therefore, we suggest that PLE can be a potential agent for prevention of skin aging. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponse

PubMed Central

Konger, Raymond L.; Derr-Yellin, Ethel; Travers, Jeffrey B.; Ocana, Jesus A.; Sahu, Ravi P.

2017-01-01

It is known that ultraviolet B (UVB) induces PPARγ ligand formation while loss of murine epidermal PPARγ (Pparg-/-epi) promotes UVB-induced apoptosis, inflammation, and carcinogenesis. PPARγ is known to suppress tumor necrosis factor-α (TNF-α) production. TNF-α is also known to promote UVB-induced inflammation, apoptosis, and immunosuppression. We show that Pparg-/-epi mice exhibit increased baseline TNF-α expression. Neutralizing Abs to TNF-α block the increased photo-inflammation and photo-toxicity that is observed in Pparg-/-epi mouse skin. Interestingly, the increase in UVB-induced apoptosis in Pparg-/-epi mice is not accompanied by a change in cyclobutane pyrimidine dimer clearance or in mutation burden. This suggests that loss of epidermal PPARγ does not result in a significant alteration in DNA repair capacity. However, loss of epidermal PPARγ results in marked immunosuppression using a contact hypersensitivity (CHS) model. This impaired CHS response was significantly alleviated using neutralizing TNF-α antibodies or loss of germline Tnf. In addition, the PPARγ agonist rosiglitazone reversed UVB-induced systemic immunosuppression (UV-IS) as well as UV-induced growth of B16F10 melanoma tumor cells in syngeneic mice. Finally, increased B16F10 tumor growth was observed when injected subcutaneously into Pparg-/-epi mice. Thus, we provide novel evidence that epidermal PPARγ is important for cutaneous immune function and the acute photoresponse. PMID:29228682

Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells

PubMed Central

Besaratinia, Ahmad; Kim, Sang-in; Pfeifer, Gerd P.

2009-01-01

Despite the predominance of UVA relative to UVB in terrestrial sunlight, solar mutagenesis in humans and rodents is characterized by mutations specific for UVB. We have investigated the kinetics of repair of UVA- and UVB-induced DNA lesions in relation to mutagenicity in transgenic mouse fibroblasts irradiated with equilethal doses of UVA and UVB in comparison to SSL. We have also analyzed mutagenesis-derived carcinogenesis in sunlight-associated human skin cancers by compiling the published data on mutation types found in crucial genes in non-melanoma and melanoma skin cancers. Here, we demonstrate a resistance to repair of UVB-induced CPDs together with rapid removal of UVA-induced oxidized purines in the genome overall and in the cII transgene of SSL-irradiated cells. The spectra of mutation induced by both UVB- and SSL-irradiation in this experimental system are characterized by significant increases in relative frequency of C to T transitions at dipyrimidines, which are the established signature mutation of CPDs. This type of mutation is also the predominant mutation found in human non-melanoma and melanoma tumor samples in the TP53, CDKN2, PTCH, and protein kinase genes. The prevailing role of UVB over UVA in solar mutagenesis in our test system can be ascribed to different kinetics of repair for lesions induced by the respective UV-irradiation. PMID:18326785

The Human Papillomavirus Type 16 E6 Gene Alone Is Sufficient To Induce Carcinomas in Transgenic Animals

PubMed Central

Song, Shiyu; Pitot, Henry C.; Lambert, Paul F.

1999-01-01

High-risk human papillomaviruses (HPVs) are the causative agents of certain human cancers. HPV type 16 (HPV16) is the papillomavirus most frequently associated with cervical cancer in women. The E6 and E7 genes of HPV are expressed in cells derived from these cancers and can transform cells in tissue culture. Animal experiments have demonstrated that E6 and E7 together cause tumors. We showed previously that E6 and E7 together or E7 alone could induce skin tumors in mice when these genes were expressed in the basal epithelia of the skin. In this study, we investigated the role that the E6 gene plays in carcinogenesis. We generated K14E6 transgenic mice, in which the HPV16 E6 gene was directed in its expression by the human keratin 14 promoter (hK14) to the basal layer of the epidermis. We found that E6 induced cellular hyperproliferation and epidermal hyperplasia and caused skin tumors in adult mice. Interestingly, the tumors derived from E6 were mostly malignant, as opposed to the tumors from E7 mice, which were mostly benign. This result leads us to hypothesize that E6 may contribute differently than E7 to HPV-associated carcinogenesis; whereas E7 primarily contributes to the early stages of carcinogenesis that lead to the formation of benign tumors, E6 primarily contributes to the late stages of carcinogenesis that lead to malignancy. PMID:10364340

Inhibition of ultraviolet-B epidermal ornithine decarboxylase induction and skin carcinogenesis in hairless mice by topical indomethacin and triamcinolone acetonide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, N.J.; Connor, M.J.; Breeding, J.

1982-10-01

Modulation of ultraviolet-B (UVB) skin carcinogenesis by topical treatment with two antiinflammatory drugs expected to have different mechanisms of action has been studied in the hairless mouse. Indomethacin is a nonsteroidal antiinflammatory agent which may act by inhibiting prostaglandin biosynthesis. Triamcinolone acetonide is a steroidal antiinflammatory agent. Both of these drugs inhibited the induction of epidermal ornithine decarboxylase by UVB when applied topically in a acetone vehicle. A UVB skin tumor study was designed. Groups of mice were irradiated daily with UVB for 20 days, each mouse receiving a total of 17.1 kJ UVB per sq m. Group 1 wasmore » treated with acetone immediately after each irradiation; Group 2 received 700 nmol indomethacin in acetone immediately after each irradiation; Group 3 received 14.4 nmol triamcinolone acetonide in acetone immediately after each irradiation. Mice were killed after 52 weeks, and the tumors were excised and examined histologically. Both topical indomethacin and topical triamcinolone acetonide were effective in reducing the incidence and size of the skin tumors induced by UVB. This evidence supports the hypothesis that the induction of ornithine decarboxylase may be a critical component of UVB skin carcinogenesis and that inhibition of ornithine decarboxylase induction can be used as a screen for agents which will inhibit UVB skin carcinogenesis.« less

Time-course study of different innate immune mediators produced by UV-irradiated skin: comparative effects of short and daily versus a single harmful UV exposure.

PubMed

Cela, Eliana M; Friedrich, Adrian; Paz, Mariela L; Vanzulli, Silvia I; Leoni, Juliana; González Maglio, Daniel H

2015-05-01

The modulatory effects of solar UV radiation on the immune system have been widely studied. As the skin is the main target of UV radiation, our purpose was to compare the impact on skin innate immunity of two contrasting ways to be exposed to sunlight. Hairless mice were UV irradiated with a single high UV dose simulating a harmful exposure, or with repetitive low UV doses simulating short occasional daily exposures. Skin samples were taken at different times after UV irradiation to evaluate skin histology, inflammatory cell recruitment, epidermal T-cell population and the mitochondrial function of epidermal cells. The transcriptional profiles of pro-inflammatory cytokines, chemokines, antimicrobial peptides and Toll-like receptors were evaluated by RT-PCR and ELISA in tissue homogenates. Finally, a lymphangiography was performed to assess modification in the lymphatic vessel system. A single high UV dose produces a deep inflammatory state characterized by the production of pro-inflammatory cytokines and chemokines that, in turn, induces the recruitment of neutrophils and macrophages into the irradiated area. On the other hand, repetitive low UV doses drive the skin to a photo-induced alert state in which there is no sign of inflammation, but the epithelium undergoes changes in thickness, the lymphatic circulation increases, and the transcription of antimicrobial peptides is induced. © 2014 John Wiley & Sons Ltd.

Human papillomaviruses and skin cancer.

PubMed

Smola, Sigrun

2014-01-01

Human papillomaviruses (HPVs) infect squamous epithelia and can induce hyperproliferative lesions. More than 120 different HPV types have been characterized and classified into five different genera. While mucosal high-risk HPVs have a well-established causal role in anogenital carcinogenesis, the biology of cutaneous HPVs is less well understood. The clinical relevance of genus beta-PV infection has clearly been demonstrated in patients suffering from epidermodysplasia verruciformis (EV), a rare inherited disease associated with ahigh rate of skin cancer. In the normal population genus beta-PV are suspected to have an etiologic role in skin carcinogenesis as well but this is still controversially discussed. Their oncogenic potency has been investigated in mouse models and in vitro. In 2009, the International Agency for Research on Cancer (IARC) classified the genus beta HPV types 5 and 8 as "possible carcinogenic" biological agents (group 2B) in EV disease. This chapter will give an overview on the knowns and unknowns of infections with genus beta-PV and discuss their potential impact on skin carcinogenesis in the general population.

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

PubMed

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.

Sunlight and Skin Cancer: Lessons from the Immune System

PubMed Central

Ullrich, Stephen E.

2009-01-01

The ultraviolet (UV) radiation in sunlight induces skin cancer development. Skin cancer is the most common form of human neoplasia. Estimates suggest that in excess of 1.5 million new cases of skin cancer (www.cancer.org/statistics) will be diagnosed in the United States this year Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer, and the cost of treating skin cancer in the United States (both melanoma and non-melanoma skin cancer) is estimated to be in excess of $2.9 billion a year. In addition to causing skin cancer, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. Recent studies in my laboratory have focused on understanding the initial molecular events that induce immune suppression. We made two novel observations: First UV-induced keratinocyte-derived platelet activating factor plays a role in the induction of immune suppression. Second, cis-urocanic acid, a skin derived immunosuppressive compound mediates immune suppression by binding to serotonin receptors on target cells. Recent findings suggest that blocking the binding of these compounds to their receptors not only inhibits UV-induced immune suppression but it also interferes with skin cancer induction. PMID:17443748

Comparative analysis of the relative potential of silver, zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis

PubMed Central

Arora, Sumit; Omar, Yousef; Ijaz, Zohaib Mohammad; AL-Ghadhban, Ahmed; Deshmukh, Sachin K.; Carter, James E.; Singh, Ajay P.; Singh, Seema

2016-01-01

Sunscreen formulations containing UVB filters, such as Zinc-oxide (ZnO) and titanium-dioxide (TiO2) nanoparticles (NPs) have been developed to limit the exposure of human skin to UV-radiations. Unfortunately, these UVB protective agents have failed in controlling the skin cancer incidence. We recently demonstrated that silver nanoparticles (Ag-NPs) could serve as novel protective agents against UVB-radiations. Here our goal was to perform comparative analysis of direct and indirect UVB-protection efficacy of ZnO-, TiO2- and Ag-NPs. Sun-protection-factor calculated based on their UVB-reflective/absorption abilities was the highest for TiO2-NPs followed by Ag- and ZnO-NPs. This was further confirmed by studying indirect protection of UVB radiation-induced death of HaCaT cells. However, only Ag-NPs were active in protecting HaCaT cells against direct UVB-induced DNA-damage by repairing bulky-DNA lesions through nucleotide-excision-repair mechanism. Moreover, Ag-NPs were also effective in protecting HaCaT cells from UVB-induced oxidative DNA damage by enhancing SOD/CAT/GPx activity. In contrast, ZnO- and TiO2-NPs not only failed in providing any direct protection from DNA-damage, but rather enhanced oxidative DNA-damage by increasing ROS production. Together, these findings raise concerns about safety of ZnO- and TiO2-NPs and establish superior protective efficacy of Ag-NPs. PMID:27693632

Gasdermin C is induced by ultraviolet light and contributes to MMP-1 expression via activation of ERK and JNK pathways.

PubMed

Kusumaningrum, Novi; Lee, Dong Hun; Yoon, Hyun-Sun; Kim, Yeon Kyung; Park, Chi-Hyun; Chung, Jin Ho

2018-05-01

Ultraviolet (UV) radiation plays important roles in various skin diseases including premature aging and cancer. UV has been shown to regulate the expressions of many genes including matrix metalloproteinases (MMPs). Gasdermin C (GSDMC) belongs to Gasdermin family and is known to be expressed in the epithelial cells of many tissues including the skin. However, the functions of GSDMC remain poorly understood. We aimed to investigate the role of GSDMC in UV-induced MMP-1, MMP-3, and MMP-9 expressions in human skin keratinocytes. Primary human skin keratinocytes and an immortalized human skin keratinocyte cell line (HaCaT cells) were irradiated with UV. Knockdown and overexpression of GSDMC were performed to study the effect of GSDMC. The mRNA and protein levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. We found that GSDMC expression is increased by UV irradiation in human skin keratinocytes. Further studies showed that GSDMC expression is increased at relatively late time points after UV irradiation and that this GSDMC induction plays important roles in the expressions of MMP-1, but not of MMP-3 and MMP-9, and the activations of ERK and JNK induced by UV. In addition, we found that overexpression of GSDMC increases the MMP-1 expression and the activities of ERK and JNK and that GSDMC-induced MMP-1 expression is suppressed by inhibition of ERK or JNK activities. Our results suggest that GSDMC is increased by UV radiation and contributes to UV-induced MMP-1 expression through the activation of ERK and JNK pathways. Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Chemopreventive apigenin controls UVB-induced cutaneous proliferation and angiogenesis through HuR and thrombospondin-1

PubMed Central

Veliceasa, Dorina; Bridgeman, Bryan B.; Fitchev, Philip; Cornwell, Mona L.; Crawford, Susan E.; Pelling, Jill C.; Volpert, Olga V.

2014-01-01

Plant flavonoid apigenin prevents and inhibits UVB-induced carcinogenesis in the skin and has strong anti-proliferative and anti-angiogenic properties. Here we identify mechanisms, by which apigenin controls these oncogenic events. We show that apigenin acts, at least in part, via endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1). TSP1 expression by the epidermal keratinocytes is potently inhibited by UVB. It inhibits cutaneous angiogenesis and UVB-induced carcinogenesis. We show that apigenin restores TSP1 in epidermal keratinocytes subjected to UVB and normalizes proliferation and angiogenesis in UVB-exposed skin. Importantly, reconstituting TSP1 anti-angiogenic function in UVB-irradiated skin with a short bioactive peptide mimetic representing exclusively its anti-angiogenic domain reproduced the anti-proliferative and anti-angiogenic effects of apigenin. Cox-2 and HIF-1α are important mediators of angiogenesis. Both apigenin and TSP1 peptide mimetic attenuated their induction by UVB. Finally we identified the molecular mechanism, whereby apigenin did not affect TSP1 mRNA, but increased de novo protein synthesis. Knockdown studies implicated the RNA-binding protein HuR, which controls mRNA stability and translation. Apigenin increased HuR cytoplasmic localization and physical association with TSP1 mRNA causing de novo TSP1 synthesis. HuR cytoplasmic localization was, in turn, dependent on CHK2 kinase. Together, our data provide a new mechanism, by which apigenin controls UVB-induced carcinogenesis. PMID:25526033

Epigenetic and genetic dissections of UV-induced global gene dysregulation in skin cells through multi-omics analyses

PubMed Central

Shen, Yao; Stanislauskas, Milda; Li, Gen; Zheng, Deyou; Liu, Liang

2017-01-01

To elucidate the complex molecular mechanisms underlying the adverse effects UV radiation (UVR) on skin homeostasis, we performed multi-omics studies to characterize UV-induced genetic and epigenetic changes. Human keratinocytes from a single donor treated with or without UVR were analyzed by RNA-seq, exome-seq, and H3K27ac ChIP-seq at 4 h and 72 h following UVR. Compared to the relatively moderate mutagenic effects of UVR, acute UV exposure induced substantial epigenomic and transcriptomic alterations, illuminating a previously underappreciated role of epigenomic and transcriptomic instability in skin pathogenesis. Integration of the multi-omics data revealed that UVR-induced transcriptional dysregulation of a subset of genes was attributable to either genetic mutations or global redistribution of H3K27ac. H3K27ac redistribution further led to the formation of distinctive super enhancers in UV-irradiated cells. Our analysis also identified several new UV target genes, including CYP24A1, GJA5, SLAMF7 and ETV1, which were frequently dysregulated in human squamous cell carcinomas, highlighting their potential as new molecular targets for prevention or treatment of UVR-induced skin cancers. Taken together, our concurrent multi-omics analyses provide new mechanistic insights into the complex molecular networks underlying UV photobiological effects, which have important implications in understanding its impact on skin homeostasis and pathogenesis. PMID:28211524

trans-Chalcone, a flavonoid precursor, inhibits UV-induced skin inflammation and oxidative stress in mice by targeting NADPH oxidase and cytokine production.

PubMed

Martinez, Renata M; Pinho-Ribeiro, Felipe A; Steffen, Vinicius S; Caviglione, Carla V; Fattori, Victor; Bussmann, Allan J C; Bottura, Carolina; Fonseca, Maria J V; Vignoli, Josiane A; Baracat, Marcela M; Georgetti, Sandra R; Verri, Waldiceu A; Casagrande, Rubia

2017-07-01

trans-Chalcone is a plant flavonoid precursor, which lacks broad investigation on its biological activity in inflammatory processes. In the present study, anti-inflammatory and antioxidant mechanisms of systemic administration with trans-chalcone, a flavonoid precursor, on ultraviolet (UV) irradiation-induced skin inflammation and oxidative stress in hairless mice were investigated by the following parameters: skin edema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, gp 91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR and cytokine production by ELISA. Systemic treatment with trans-chalcone inhibited skin inflammation by reducing skin edema and neutrophil recruitment, and also inhibited matrix metalloproteinase-9 activity. trans-Chalcone also inhibited oxidative stress, gp 91phox mRNA expression, and the production of a wide range of pro-inflammatory cytokines, while it did not affect anti-inflammatory cytokines induced by UV irradiation. However, trans-chalcone did not prevent oxidative stress in vitro, suggesting that its in vivo effect is more related to anti-inflammatory properties rather than a direct antioxidant effect. In conclusion, treatment with trans-chalcone inhibited UV-induced skin inflammation resulting in oxidative stress inhibition in vivo. Therefore, systemic supplementation with this compound may represent an important therapeutic approach in inflammatory skin diseases induced by UV irradiation.

Dermal damage promoted by repeated low-level UV-A1 exposure despite tanning response in human skin.

PubMed

Wang, Frank; Smith, Noah R; Tran, Bao Anh Patrick; Kang, Sewon; Voorhees, John J; Fisher, Gary J

2014-04-01

Solar UV irradiation causes photoaging, characterized by fragmentation and reduced production of type I collagen fibrils that provide strength to skin. Exposure to UV-B irradiation (280-320 nm) causes these changes by inducing matrix metalloproteinase 1 and suppressing type I collagen synthesis. The role of UV-A irradiation (320-400 nm) in promoting similar molecular alterations is less clear yet important to consider because it is 10 to 100 times more abundant in natural sunlight than UV-B irradiation and penetrates deeper into the dermis than UV-B irradiation. Most (approximately 75%) of solar UV-A irradiation is composed of UV-A1 irradiation (340-400 nm), which is also the primary component of tanning beds. To evaluate the effects of low levels of UV-A1 irradiation, as might be encountered in daily life, on expression of matrix metalloproteinase 1 and type I procollagen (the precursor of type I collagen). In vivo biochemical analyses were conducted after UV-A1 irradiation of normal human skin at an academic referral center. Participants included 22 healthy individuals without skin disease. Skin pigmentation was measured by a color meter (chromometer) under the L* variable (luminescence), which ranges from 0 (black) to 100 (white). Gene expression in skin samples was assessed by real-time polymerase chain reaction. Lightly pigmented human skin (L* >65) was exposed up to 4 times (1 exposure/d) to UV-A1 irradiation at a low dose (20 J/cm2), mimicking UV-A levels from strong sun exposure lasting approximately 2 hours. A single exposure to low-dose UV-A1 irradiation darkened skin slightly and did not alter matrix metalloproteinase 1 or type I procollagen gene expression. With repeated low-dose UV-A1 irradiation, skin darkened incrementally with each exposure. Despite this darkening, 2 or more exposures to low-dose UV-A1 irradiation significantly induced matrix metalloproteinase 1 gene expression, which increased progressively with successive exposures. Repeated UV-A1 exposures did not suppress type I procollagen expression. A limited number of low-dose UV-A1 exposures, as commonly experienced in daily life, potentially promotes photoaging by affecting breakdown, rather than synthesis, of collagen. Progressive skin darkening in response to repeated low-dose UV-A1 exposures in lightly pigmented individuals does not prevent UV-A1-induced collagenolytic changes. Therefore, for optimal protection against skin damage, sunscreen formulations should filter all UV wavelengths, including UV-A1 irradiation.

Anticancer Effects of Sandalwood (Santalum album).

PubMed

Santha, Sreevidya; Dwivedi, Chandradhar

2015-06-01

Effective management of tumorigenesis requires development of better anticancer agents with greater efficacy and fewer side-effects. Natural products are important sources for the development of chemotherapeutic agents and almost 60% of anticancer drugs are of natural origin. α-Santlol, a sesquiterpene isolated from Sandalwood, is known for a variety of therapeutic properties including anti-inflammatory, anti-oxidant, anti-viral and anti-bacterial activities. Cell line and animal studies reported chemopreventive effects of sandalwood oil and α-santalol without causing toxic side-effects. Our laboratory identified its anticancer effects in chemically-induced skin carcinogenesis in CD-1 and SENCAR mice, ultraviolet-B-induced skin carcinogenesis in SKH-1 mice and in vitro models of melanoma, non-melanoma, breast and prostate cancer. Its ability to induce cell-cycle arrest and apoptosis in cancer cells is its most reported anticancer mechanism of action. The present review discusses studies that support the anticancer effect and the mode of action of sandalwood oil and α-santalol in carcinogenesis. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Daily Ingestion of Aloe Vera Gel Powder Containing Aloe Sterols Prevents Skin Photoaging in OVX Hairless Mice.

PubMed

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

2016-10-12

Estrogen deficiencies associated with menopause accelerate spontaneous skin aging and stimulate the ultraviolet (UV) irradiation-induced photoaging of skin. However, food compositions with the potential to ameliorate the UV irradiation-induced acceleration of skin aging with menopause have not yet been investigated in detail. In the present study, we examined the ability of plant sterols derived from Aloe vera gel to prevent the UV irradiation-induced acceleration of skin aging in ovariectomized mice. Skin transepidermal water loss (TEWL) was significantly higher in the ovariectomy group than in the sham operation group following UVB irradiation, whereas skin elasticity was significantly lower. Ultraviolet B (UVB) irradiation induced greater reductions in skin hyaluronic acid levels and more severe collagen fiber damage in the derims in the ovariectomy group than in the sham group. The intake of AVGP significantly ameliorated this acceleration in skin aging by reducing the expression of matrix metalloproteinases (MMPs) and increasing that of epidermal growth factor (EGF) and hyaluronan synthase (HAS) in the skin. These results indicate that AVGP supplementation prevents skin damage induced by UVB irradiation and ovariectomy in part by inhibiting damage to the extracellular matrix. © 2016 Institute of Food Technologists®.

Caspase 3 promotes genetic instability and carcinogenesis

PubMed Central

Liu, Xinjian; He, Yujun; Li, Fang; Huang, Qian; Kato, Takamitsu A.; Hall, Russell P; Li, Chuan-Yuan

2015-01-01

Summary Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase 3, facilitates, rather than suppresses, chemical and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive, despite caspase 3 activation. Moreover, this sublethal activation of caspase 3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically-induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase 3. Furthermore, attenuation of Endo G activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying Endo G as a downstream effector of caspase 3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase 3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage. PMID:25866249

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

PubMed Central

Shin, Mi Hee; Lee, Se-Rah; Kim, Min-Kyoung; Shin, Chang-Yup

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. PMID:27611371

Bioconvertible vitamin antioxidants improve sunscreen photoprotection against UV-induced reactive oxygen species.

PubMed

Hanson, Kerry M; Clegg, Robert M

2003-01-01

The ability of sunscreens and antioxidants to deactivate highly destructive reactive oxygen species in human skin has remained inconclusive. Two-photon fluorescence imaging microscopy was used to determine the effect of sunscreen/antioxidant combinations upon UV-induced ROS generation in ex vivo human skin. A sunscreen combination containing octylmethoxycinnamate (Parsol MCX) and avobenzone (Parsol 1789) at SPF 8 and SPF 15 was tested for its ability to prevent UV radiation from generating ROS in the viable epidermal strata of ex vivo human skin. A UV dose equivalent to two hours of North American solar UV was used to irradiate the skin. Each sunscreen reduced the amount of ROS induced in the viable strata by a value consistent with the SPF level. UV photons that were not absorbed/scattered by the sunscreen formulations generated ROS within the viable epidermal layers. The addition of the bioconvertible antioxidants vitamin E acetate and sodium ascorbyl phosphate (STAY-C 50) improves photoprotection by converting to vitamins E and C, respectively, within the skin. The bioconversion forms an antioxidant reservoir that deactivates the ROS generated (within the strata granulosum, spinosum, and basale) by the UV photons that the sunscreens do not block in the stratum corneum.

Protective effect of chromene isolated from Sargassum horneri against UV-A-induced damage in skin dermal fibroblasts.

PubMed

Kim, Jung-Ae; Ahn, Byul-Nim; Kong, Chang-Suk; Kim, Se-Kwon

2012-08-01

Skin homoeostasis is interrupted during UV-A irradiation. How the UV-A-altered skin components influences photoageing of skin should be investigated using human in vitro models that are important for understanding skin ageing. In this study, chromene compound, sargachromenol, was isolated from Sargassum horneri, and its potency on inhibition of photoageing was investigated in UV-A-irradiated dermal fibroblasts. Effects of sargachromenol on the prevention of photoageing were evaluated by measuring ROS production, membrane protein oxidation, lipid peroxidation and ageing-related gene expression in UV-A-irradiated human skin dermal fibroblasts. The results indicated that treatment with sargachromenol suppressed the collagenase matrix metalloproteinases (MMPs), MMP-1, MMP-2 and MMP-9 expression without any cytotoxicity and phototoxicity. It was further found that these inhibitions were because of increase in the expression of TIMP-1 and TIMP-2 genes. Furthermore, we confirmed that the UV-A-induced transcriptions of AP-1 signalling pathway were regulated by sargachromenol treatment in UV-A-irradiated dermal fibroblasts. © 2012 John Wiley & Sons A/S.

Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite.

PubMed

Ahlborn, Gene J; Nelson, Gail M; Ward, William O; Knapp, Geremy; Allen, James W; Ouyang, Ming; Roop, Barbara C; Chen, Yan; O'Brien, Thomas; Kitchin, Kirk T; Delker, Don A

2008-03-15

Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips, and pathway analysis was conducted with DAVID (NIH), Ingenuity Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.

Irradiation of skin with visible light induces reactive oxygen species and matrix-degrading enzymes.

PubMed

Liebel, Frank; Kaur, Simarna; Ruvolo, Eduardo; Kollias, Nikiforos; Southall, Michael D

2012-07-01

Daily skin exposure to solar radiation causes cells to produce reactive oxygen species (ROS), which are a primary factor in skin damage. Although the contribution of the UV component to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology. Solar radiation comprises <10% of UV, and thus the purpose of this study was to examine the physiological response of skin to visible light (400-700 nm). Irradiation of human skin equivalents with visible light induced production of ROS, proinflammatory cytokines, and matrix metalloproteinase (MMP)-1 expression. Commercially available sunscreens were found to have minimal effects on reducing visible light-induced ROS, suggesting that UVA/UVB sunscreens do not protect the skin from visible light-induced responses. Using clinical models to assess the generation of free radicals from oxidative stress, higher levels of free radical activity were found after visible light exposure. Pretreatment with a photostable UVA/UVB sunscreen containing an antioxidant combination significantly reduced the production of ROS, cytokines, and MMP expression in vitro, and decreased oxidative stress in human subjects after visible light irradiation. Taken together, these findings suggest that other portions of the solar spectrum aside from UV, particularly visible light, may also contribute to signs of premature photoaging in skin.

Solar ultraviolet radiation induces biological alterations in human skin in vitro: relevance of a well-balanced UVA/UVB protection.

PubMed

Bernerd, Francoise; Marionnet, Claire; Duval, Christine

2012-06-01

Cutaneous damages such as sunburn, pigmentation, and photoaging are known to be induced by acute as well as repetitive sun exposure. Not only for basic research, but also for the design of the most efficient photoprotection, it is crucial to understand and identify the early biological events occurring after ultraviolet (UV) exposure. Reconstructed human skin models provide excellent and reliable in vitro tools to study the UV-induced alterations of the different skin cell types, keratinocytes, fibroblasts, and melanocytes in a dose- and time-dependent manner. Using different in vitro human skin models, the effects of UV light (UVB and UVA) were investigated. UVB-induced damages are essentially epidermal, with the typical sunburn cells and DNA lesions, whereas UVA radiation-induced damages are mostly located within the dermal compartment. Pigmentation can also be obtained after solar simulated radiation exposure of pigmented reconstructed skin model. Those models are also highly adequate to assess the potential of sunscreens to protect the skin from UV-associated damage, sunburn reaction, photoaging, and pigmentation. The results showed that an effective photoprotection is provided by broad-spectrum sunscreens with a potent absorption in both UVB and UVA ranges.

UV-induced inhibition of adipokine production in subcutaneous fat aggravates dermal matrix degradation in human skin.

PubMed

Kim, Eun Ju; Kim, Yeon Kyung; Kim, Min-Kyoung; Kim, Sungsoo; Kim, Jin Yong; Lee, Dong Hun; Chung, Jin Ho

2016-05-10

Ultraviolet (UV) exposure to the human skin reduces triglycerides contents and lipid synthesis in the subcutaneous (SC) fat. Because adiponectin and leptin are the most abundant adipokines from the SC fat, we aim to investigate how they interact with UV exposure and skin aging. The expressions of adiponectin and leptin were significantly decreased in SC fat of sun-exposed forearm skin, in comparison with that of sun-protected buttock skin of the same elderly individuals, indicating that chronic UV exposure decreases both adipokines. Acute UV irradiation also decreased the expressions of adiponectin and leptin in SC fat. The expressions of adiponectin receptor 1/2 and leptin receptor were significantly decreased in the dermis as well as in SC fat. Moreover, while exogenous adiponectin and leptin administration prevented UV- and TNF-α induced matrix metalloproteinase (MMP)-1 expression, they also increased UV- and TNF-α induced reduction of type 1 procollagen production. Silencing of adiponectin, leptin or their receptors led to an increased MMP-1 and a decreased type 1 procollagen expression, which was reversed by treatment with recombinant human adiponectin or leptin. In conclusion, UV exposure decreases the expression of adiponectin and leptin, leading to the exacerbation of photoaging by stimulating MMP-1 expression and inhibiting procollagen synthesis.

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

PubMed

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.

Photobiological implications of melanin photoprotection after UVB-induced tanning of human skin but not UVA-induced tanning.

PubMed

Coelho, Sergio G; Yin, Lanlan; Smuda, Christoph; Mahns, Andre; Kolbe, Ludger; Hearing, Vincent J

2015-03-01

Repetitive suberythemal UVA and/or UVB exposures were used to generate comparable UV-induced tans in human skin over the course of 2 weeks. To evaluate the potential photoprotective values of those UVA- and/or UVB- induced tans and to avoid the confounding issue of residual UV-induced DNA damage, we waited 1 week before challenging those areas with a 1.5 MED of UVA+UVB after which we measure DNA damage. The results show that the type of UV used to induce skin pigmentation affects the redistribution of melanin in the skin and/or de novo melanin synthesis. The UVA-induced tans failed to even provide a minimal SPF of 1.5, which suggests that producing a tan with UVA-rich sunlamps prior to a holiday or vacation is completely counterproductive. Published 2014. This article is a US Government work and is in the public domain in the USA.

The repair of low dose UV light-induced damage to human skin DNA in condition of trace amount Mg 2+

NASA Astrophysics Data System (ADS)

Gao, Fang; Guo, Zhouyi; Zheng, Changchun; Wang, Rui; Liu, Zhiming; Meng, Pei; Zhai, Juan

2008-12-01

Ultraviolet light-induced damage to human skin DNA was widely investigated. The primary mechanism of this damage contributed to form cyclobutane pyrimidine dimmers (CPDs). Although the distribution of UV light-induced CPDs within a defined sequence is similar, the damage in cellular environment which shields the nuclear DNA was higher than that in organism in apparent dose. So we use low UVB light as main study agent. Low dose UV-irradiated HDF-a cells (Human Dermal Fibroblasts-adult cells) which is weaker than epidermic cells were cultured with DMEM at different trace amount of Mg2+ (0mmol/L , 0.1mmol/L , 0.2mmol/L, 0.4mmol/L, 0.8mmol/L, 1.2mmol/L) free-serum DMEM and the repair of DNA strands injured were observed. Treat these cells with DNA strand breaks detection, photoproducts detection and the repair of photoproducts detection. Then quantitate the role of trace amount Mg2+ in repair of UV light-induced damage to human skin. The experiment results indicated that epidermic cells have capability of resistance to UV-radiation at a certain extent. And Mg2+ can regulate the UV-induced damage repair and relative vitality. It can offer a rationale and experiment data to relieve UV light-induced skin disease.

An essential role for platelet-activating factor in activating mast cell migration following ultraviolet irradiation

PubMed Central

Chacón-Salinas, Rommel; Chen, Limo; Chávez-Blanco, Alma D.; Limón-Flores, Alberto Y.; Ma, Ying; Ullrich, Stephen E.

2014-01-01

The UVB (290–320 nm) radiation in sunlight is responsible for inducing skin cancer. Exposure to UV radiation is also immunosuppressive, and the systemic immune suppression induced by UV is a well-recognized risk factor for cancer induction. As UVB radiation is absorbed within the upper layers of the skin, indirect mechanisms must play a role in activating systemic immune suppression. One prominent example is mast cell migration, which from the skin to the draining LN is an essential step in the cascade of events leading to immune suppression. What triggers mast cell migration is not entirely clear. Here, we tested the hypothesis that PAF, a lipid mediator of inflammation produced by the skin in response to UV exposure, is involved. Mast cell-deficient mice (KitW-sh/W-sh) are resistant to the suppressive effect of UV radiation, and reconstituting mast cell-deficient mice with normal bone marrow-derived mast cells restores susceptibility to immunosuppression. However, when mast cells from PAFR−/− mice were used, the reconstituted mice were not susceptible to the suppressive effects of UV. Furthermore, PAFR−/− mice showed impaired UV-induced mast cell migration when compared with WT mice. Finally, injecting PAF into WT mice mimicked the effect of UV irradiation and induced mast cell migration but not in PAFR−/− mice. Our findings indicate that PAFR binding induces mast cells to migrate from the skin to the LNs, where they mediate immune suppression. PMID:24009177

Nicotinamide Enhances Repair of Arsenic and Ultraviolet Radiation-Induced DNA Damage in HaCaT Keratinocytes and Ex Vivo Human Skin

PubMed Central

Thompson, Benjamin C.; Halliday, Gary M.; Damian, Diona L.

2015-01-01

Arsenic-induced skin cancer is a significant global health burden. In areas with arsenic contamination of water sources, such as China, Pakistan, Myanmar, Cambodia and especially Bangladesh and West Bengal, large populations are at risk of arsenic-induced skin cancer. Arsenic acts as a co-carcinogen with ultraviolet (UV) radiation and affects DNA damage and repair. Nicotinamide (vitamin B3) reduces premalignant keratoses in sun-damaged skin, likely by prevention of UV-induced cellular energy depletion and enhancement of DNA repair. We investigated whether nicotinamide modifies DNA repair following exposure to UV radiation and sodium arsenite. HaCaT keratinocytes and ex vivo human skin were exposed to 2μM sodium arsenite and low dose (2J/cm2) solar-simulated UV, with and without nicotinamide supplementation. DNA photolesions in the form of 8-oxo-7,8-dihydro-2′-deoxyguanosine and cyclobutane pyrimidine dimers were detected by immunofluorescence. Arsenic exposure significantly increased levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine in irradiated cells. Nicotinamide reduced both types of photolesions in HaCaT keratinocytes and in ex vivo human skin, likely by enhancing DNA repair. These results demonstrate a reduction of two different photolesions over time in two different models in UV and arsenic exposed cells. Nicotinamide is a nontoxic, inexpensive agent with potential for chemoprevention of arsenic induced skin cancer. PMID:25658450

Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development.

PubMed

Lee, Hyunseung; Kim, Mihwa; Baek, Minwoo; Morales, Liza D; Jang, Ik-Soon; Slaga, Thomas J; DiGiovanni, John; Kim, Dae Joon

2017-03-21

Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2 fl/fl ) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling.

Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development

PubMed Central

Lee, Hyunseung; Kim, Mihwa; Baek, Minwoo; Morales, Liza D.; Jang, Ik-Soon; Slaga, Thomas J.; DiGiovanni, John; Kim, Dae Joon

2017-01-01

Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling. PMID:28322331

Size is an essential parameter in governing the UVB-protective efficacy of silver nanoparticles in human keratinocytes.

PubMed

Palanki, Rohan; Arora, Sumit; Tyagi, Nikhil; Rusu, Lilia; Singh, Ajay P; Palanki, Srinivas; Carter, James E; Singh, Seema

2015-09-15

Ultraviolet (UV) radiation from sun, particularly its UVB component (290-320 nm), is considered the major etiological cause of skin cancer that impacts over 2 million lives in the United States alone. Recently, we reported that polydisperse colloidal suspension of silver nanoparticles (AgNPs) protected the human keratinocytes (HaCaT) against UVB-induced damage, thus indicating their potential for prevention of skin carcinogenesis. Here we sought out to investigate if size controlled the chemopreventive efficacy of AgNPs against UVB-induced DNA damage and apoptosis. Percent cell viability was examined by WST-1 assay after treating the cells with various doses (1-10 μg/mL) of AgNPs of different sizes (10, 20, 40, 60 and 100 nm) for 12 and 24 h. For protection studies, cells were treated with AgNPs of different sizes at a uniform concentration of 1 μg/mL. After 3 h, cells were irradiated with UVB (40 mJ/cm(2)) and dot-blot analysis was performed to detect cyclobutane pyrimidine dimers (CPDs) as an indication of DNA damage. Apoptosis was analyzed by flow cytometry after staining the cells with 7-Amino-Actinomycin (7-AAD) and PE Annexin V. Immunoblot analysis was accomplished by processing the cells for protein extraction and Western blotting using specific antibodies against various proteins. The data show that the pretreatment of HaCaT cells with AgNPs in the size range of 10-40 nm were effective in protecting the skin cells from UVB radiation-induced DNA damage as validated by reduced amounts of CPDs, whereas no protection was observed with AgNPs of larger sizes (60 and 100 nm). Similarly, only smaller size AgNPs (10-40 nm) were effective in protecting the skin cells from UV radiation-induced apoptosis. At the molecular level, UVB -irradiation of HaCaT cells led to marked increase in expression of pro-apoptotic protein (Bax) and decrease in anti-apoptotic proteins (Bcl-2 and Bcl-xL), while it remained largely unaffected in skin cells pretreated with smaller size AgNPs (10-40 nm). Altogether, these findings suggest that size is a critical determinant of the UVB-protective efficacy of AgNPs in human keratinocytes.

The Malassezia genus in skin and systemic diseases.

PubMed

Gaitanis, Georgios; Magiatis, Prokopios; Hantschke, Markus; Bassukas, Ioannis D; Velegraki, Aristea

2012-01-01

In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis.

The Malassezia Genus in Skin and Systemic Diseases

PubMed Central

Magiatis, Prokopios; Hantschke, Markus; Bassukas, Ioannis D.; Velegraki, Aristea

2012-01-01

Summary: In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis. PMID:22232373

Adipochemokines induced by ultraviolet irradiation contribute to impaired fat metabolism in subcutaneous fat cells.

PubMed

Kim, E J; Kim, Y K; Kim, S; Kim, J E; Tian, Y D; Doh, E J; Lee, D H; Chung, J H

2018-02-01

Adipose tissue is now appreciated as the pivotal regulator of metabolic and endocrine functions. Subcutaneous (SC) fat, in contrast to visceral fat, may protect against metabolic syndrome and systemic inflammation. We demonstrated that chronic as well as acute ultraviolet (UV) irradiation to the skin induces loss of underlying SC fat. UV-irradiated SC fat may produce chemokines or cytokines that modulate lipid homeostasis and secretion of adipokines. To elucidate UV-induced specific adipochemokines implicated in UV-induced modulation of SC fat. Primary cultured adipocytes were treated with conditioned medium from UV- or sham-irradiated skin cells. Young and older healthy participants provided SC fat from sun-exposed and sun-protected skin. Sun-protected skin from other participants was irradiated with UV. Differentially expressed adipochemokines were screened by cytokine array, and confirmed in vitro and in vivo. The functions of select adipochemokines involved in lipid metabolism were examined via short interfering RNA-mediated knockdown of cognate receptors. Specific adipochemokines, including C-X-C motif chemokine (CXCL) family members such as CXCL5/ENA-78, and C-C motif chemokine (CCL) family members such as CCL20/MIP-3α and CCL5/RANTES, were greatly induced in SC fat by UV exposure. They could impair triglyceride synthesis via downregulation of lipogenic enzymes and sterol regulatory element-binding protein-1 through their respective cognate receptors, CXC chemokine receptor type (CXC-R)2, C-C chemokine receptor type (CCR)-6, and CCR-5. In addition, UV irradiation induced infiltration of adipose tissue macrophages responsible for the secretion of several chemokines into SC fat. These UV-induced adipochemokines may be implicated in the reduction of lipogenesis in SC fat, leading to impairment of fat homeostasis and associated comorbidities such as obesity. © 2017 British Association of Dermatologists.

Transcription coupled repair deficiency protects against human mutagenesis and carcinogenesis: Personal Reflections on the 50th anniversary of the discovery of xeroderma pigmentosum.

PubMed

Cleaver, James E

2017-10-01

Xeroderma pigmentosum (XP) patients who lack the main damage recognition protein for global genome repair (GGR), XPC, have greatly increased skin cancer rates and elevated mutation frequencies originating from unrepaired ultraviolet photoproducts in the nontranscribed regions of the genome and in nontranscribed strands of expressed genes. But they show no increased mutations in transcribed strands. In contrast, cancer is absent from Cockayne syndrome (CS) patients that have defective transcription coupled repair (TCR) despite severe photosensitivity, CS patients remarkably show no elevation of UV induced mutagenesis implying that defective TCR may be protective against mutagenesis and carcinogenesis. Mutation avoidance in CS is postulated to occur through arrested transcription that generates a tripled stranded R loop consisting of DNA double strands and a nascent mRNA strand. R loops result in S phase apoptosis or activation of ATM kinase that causes a delay in DNA replication until TCR, or transcript cleavage by TFIIS or RNAaseH, relieves the transcription block. Resumption of replication then occurs on repaired DNA without concomitant mutagenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Silymarin Protects Epidermal Keratinocytes from Ultraviolet Radiation-Induced Apoptosis and DNA Damage by Nucleotide Excision Repair Mechanism

PubMed Central

Katiyar, Santosh K.; Mantena, Sudheer K.; Meeran, Syed M.

2011-01-01

Solar ultraviolet (UV) radiation is a well recognized epidemiologic risk factor for melanoma and non-melanoma skin cancers. This observation has been linked to the accumulation of UVB radiation-induced DNA lesions in cells, and that finally lead to the development of skin cancers. Earlier, we have shown that topical treatment of skin with silymarin, a plant flavanoid from milk thistle (Silybum marianum), inhibits photocarcinogenesis in mice; however it is less understood whether chemopreventive effect of silymarin is mediated through the repair of DNA lesions in skin cells and that protect the cells from apoptosis. Here, we show that treatment of normal human epidermal keratinocytes (NHEK) with silymarin blocks UVB-induced apoptosis of NHEK in vitro. Silymarin reduces the amount of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers (CPDs) and as measured by comet assay, and that ultimately may lead to reduced apoptosis of NHEK. The reduction of UV radiation-induced DNA damage by silymarin appears to be related with induction of nucleotide excision repair (NER) genes, because UV radiation-induced apoptosis was not blocked by silymarin in NER-deficient human fibroblasts. Cytostaining and dot-blot analysis revealed that silymarin repaired UV-induced CPDs in NER-proficient fibroblasts from a healthy individual but did not repair UV-induced CPD-positive cells in NER-deficient fibroblasts from patients suffering from xeroderma pigmentosum complementation-A disease. Similarly, immunohistochemical analysis revealed that silymarin did not reduce the number of UVB-induced sunburn/apoptotic cells in the skin of NER-deficient mice, but reduced the number of sunburn cells in their wild-type counterparts. Together, these results suggest that silymarin exert the capacity to reduce UV radiation-induced DNA damage and, thus, prevent the harmful effects of UV radiation on the genomic stability of epidermal cells. PMID:21731736

Photochemoprevention of UVB-induced skin carcinogenesis in SKH-1 mice by brown algae polyphenols.

PubMed

Hwang, Hyejeong; Chen, Tong; Nines, Ronald G; Shin, Hyeon-Cheol; Stoner, Gary D

2006-12-15

Chronic exposure of the skin to ultraviolet B (UVB) radiation induces oxidative stress, which plays a crucial role in the induction of skin cancer. In this study, the effect of dietary feeding and topical application of brown algae polyphenols on UVB radiation-induced skin carcinogenesis in SKH-1 mice was investigated. SKH-1 hairless mice were randomly divided into 9 groups, including control, UVB control and treatment groups. They were treated orally (0.1% and 0.5% with AIN-76 diet, w/w) and topically (3 and 6 mg/0.2 ml of vehicle) with brown algae polyphenols and irradiated with UVB for 26 weeks. Dietary feeding (0.1% and 0.5%) of brown algae polyphenols significantly reduced tumor multiplicity (45% and 56%) and tumor volume (54% and 65%), and topical administration (3 and 6 mg) significantly decreased tumor multiplicity (60% and 46%) and tumor volume (66% and 57%), respectively, per tumor-bearing mouse. Dietary feeding and topical administration of the polyphenols also inhibited tumor incidence by 6% and 21%, respectively, but the results were not significant. Dietary and topical administration of the polyphenols markedly inhibited cyclooxygenase-2 activity and cell proliferation. These observations show that brown algae polyphenols have an antiphotocarcinogenic effect which may be associated with the prevention of UVB-induced oxidative stress, inflammation, and cell proliferation in the skin. Copyright 2006 Wiley-Liss, Inc.

Photodynamic therapy does not induce cyclobutane pyrimidine dimers in the presence of melanin.

PubMed

Mudambi, Shaila; Pera, Paula; Washington, Deschana; Remenyik, Eva; Fidrus, Eszter; Shafirstein, Gal; Bellnier, David; Paragh, Gyorgy

2018-04-24

Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive oxygen species (ROS). Cyclobutane pyrimidine dimers (CPDs) are the most important DNA changes responsible for ultraviolet (UV) carcinogenesis. Recently ROS induced by UVA were shown to generate CPDs via activating melanin. This raised the possibility that PDT induced ROS may also induce CPDs and mutagenesis in melanin containing cells. Previously the effect of PDT on CPDs in melanin containing cells has not been assessed. Our current work aimed to compare the generation of CPDs in melanin containing cells subjected to UVA treatment and porfimer sodium red light PDT. We used ELISA to detect CPDs. After UVA we found a dose dependent increase in CPDs in melanoma cells (B16-F10, MNT-1) with CPD levels peaking hours after discontinuation of UVA treatment. This indicated the generation of UVA induced dark-CPDs in the model. Nevertheless, PDT in biologically relevant doses was unable to induce CPDs. Our work provides evidence for the lack of CPD generation by PDT in melanin containing cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Protective effect of skin-derived precursors on photoaging in nude mice.

PubMed

Wang, Siyu; Zhong, Jianqiao; Li, Li

2018-06-25

Currently, innovative methods to prevent photoaging are needed. Skin-derived precursors (SKP) have been shown to play a crucial role in resisting UVB-induced apoptosis in vitro. The objective of this study was to explore the effect of SKP on preventing skin photoaging in vivo. Skin-derived precursors from neonatal BALB/c mice were isolated, identified and intradermally transplanted with a PKH26 label to track their survival. These were then injected at different concentrations into the buttock dermis of nude mice at 2-weekly intervals before UV irradiation. Photographs, assessment of live skin surface, histology with quantitative real-time polymerase chain reaction and immunohistochemistry were used to evaluate the impact of SKP on wrinkles and other relevant indicators of skin photoaging. SKP exhibited a sphere-like structure and could survive for at least 2 weeks after intradermal transplantation. A large dose of SKP transplantation (10 5 SKP +UV) at 2-weekly intervals were able to ameliorate coarse UV-induced wrinkles. Moreover, the skin smoothness value, dermal thickness and collagen percentage were significantly increased in mice that received a large dose of SKP (10 5 SKP +UV). UV radiation induced the mRNA expression of MMP-13 and decreased the mRNA and protein expression of TβRII, but these effects were diminished by SKP transplantation. The transplantation of SKP could increase the mRNA of TIMP-1. We found that transplanted SKP exert a beneficial impact on preventing UV-induced wrinkles in vivo, suggesting that SKP transplantation is a promising candidate for preventing photoaging. © 2018 The Australasian College of Dermatologists.

Comparative analysis of the relative potential of silver, Zinc-oxide and titanium-dioxide nanoparticles against UVB-induced DNA damage for the prevention of skin carcinogenesis.

PubMed

Tyagi, Nikhil; Srivastava, Sanjeev K; Arora, Sumit; Omar, Yousef; Ijaz, Zohaib Mohammad; Al-Ghadhban, Ahmed; Deshmukh, Sachin K; Carter, James E; Singh, Ajay P; Singh, Seema

2016-12-01

Sunscreen formulations containing UVB filters, such as Zinc-oxide (ZnO) and titanium-dioxide (TiO 2 ) nanoparticles (NPs) have been developed to limit the exposure of human skin to UV-radiations. Unfortunately, these UVB protective agents have failed in controlling the skin cancer incidence. We recently demonstrated that silver nanoparticles (Ag-NPs) could serve as novel protective agents against UVB-radiations. Here our goal was to perform comparative analysis of direct and indirect UVB-protection efficacy of ZnO-, TiO 2 - and Ag-NPs. Sun-protection-factor calculated based on their UVB-reflective/absorption abilities was the highest for TiO 2 -NPs followed by Ag- and ZnO-NPs. This was further confirmed by studying indirect protection of UVB radiation-induced death of HaCaT cells. However, only Ag-NPs were active in protecting HaCaT cells against direct UVB-induced DNA-damage by repairing bulky-DNA lesions through nucleotide-excision-repair mechanism. Moreover, Ag-NPs were also effective in protecting HaCaT cells from UVB-induced oxidative DNA damage by enhancing SOD/CAT/GPx activity. In contrast, ZnO- and TiO 2 -NPs not only failed in providing any direct protection from DNA-damage, but rather enhanced oxidative DNA-damage by increasing ROS production. Together, these findings raise concerns about safety of ZnO- and TiO 2 -NPs and establish superior protective efficacy of Ag-NPs. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

UV-generated free radicals (FR) in skin: Their prevention by sunscreens and their induction by self-tanning agents

NASA Astrophysics Data System (ADS)

Jung, K.; Seifert, M.; Herrling, Th.; Fuchs, J.

2008-05-01

In the past few years, the cellular effects of ultraviolet (UV) irradiation induced in skin have become increasingly recognized. Indeed, it is now well known that UV irradiation induces structural and cellular changes in all the compartments of skin tissue. The generation of reactive oxygen species (ROS) is the first and immediate consequence of UV exposure and therefore the quantitative determination of free radical reactions in the skin during UV radiation is of primary importance for the understanding of dermatological photodamage. The RSF method (radical sun protection factor) herein presented, based on electron spin resonance spectroscopy (ESR), enables the measurement of free radical reactions in skin biopsies directly during UV radiation. The amount of free radicals varies with UV doses and can be standardized by varying UV irradiance or exposure time. The RSF method allows the determination of the protective effect of UV filters and sunscreens as well as the radical induction capacity of self-tanning agents as dihydroxyacetone (DHA). The reaction of the reducing sugars used in self-tanning products and amino acids in the skin layer (Maillard reaction) leads to the formation of Amadori products that generate free radicals during UV irradiation. Using the RSF method three different self-tanning agents were analyzed and it was found, that in DHA-treated skin more than 180% additional radicals were generated during sun exposure with respect to untreated skin. For this reason the exposure duration in the sun must be shortened when self-tanners are used and photoaging processes are accelerated.

Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression

PubMed Central

Kang, Nam Joo; Lee, Ki Won; Shin, Bong Jik; Jung, Sung Keun; Hwang, Mun Kyung; Bode, Ann M.; Heo, Yong-Seok; Dong, Zigang

2009-01-01

Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. In this study, we found that Fyn, one of the members of the non-receptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (COX-2) expression, and caffeic acid suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. Caffeic acid more effectively suppressed UVB-induced COX-2 expression and subsequent prostaglandin E2 production in JB6 P+ mouse skin epidermal (JB6 P+) cells compared with chlorogenic acid (5-O-caffeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-κB transcription activity compared with chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein kinases (MAPKs) were subsequently blocked. Pharmacological Fyn kinase inhibitor (3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and leflunomide) data also revealed that Fyn is involved in UVB-induced COX-2 expression mediated through the phosphorylation of MAPKs in JB6 P+ cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and non-competitively with adenosine triphosphate. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity. These results suggested that this compound could act as a potent chemopreventive agent against skin cancer. PMID:19073879

Effects of collagen and collagen hydrolysate from jellyfish (Rhopilema esculentum) on mice skin photoaging induced by UV irradiation.

PubMed

Zhuang, Yongliang; Hou, Hu; Zhao, Xue; Zhang, Zhaohui; Li, Bafang

2009-08-01

Collagen (JC) was extracted from jellyfish (Rhopilema esculentum) and hydrolyzed to prepare collagen hydrolysate (JCH). The protective effects of JC and JCH against UV-induced damages to mice skin were evaluated and compared in this article. JC and JCH could alleviate the UV-induced abnormal changes of antioxidative indicators, including the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities and the contents of glutathione (GSH) and malondiaidehyde (MDA). JC and JCH could protect skin lipid and collagen from the UV radiation damages. Furthermore, the changes of total ceramide and glycosaminoglycan in skin were recovered significantly by JC and JCH. The action mechanisms mainly involved the antioxidative properties and the repairing to endogenous collagen synthesis of JC and JCH in vivo. JCH with the lower molecular weight showed much higher effects than JC. The results indicated that JCH was a novel antiphotoaging agent from natural resources.

The effects of grape seeds polyphenols on SKH-1 mice skin irradiated with multiple doses of UV-B.

PubMed

Filip, Adriana; Daicoviciu, Doina; Clichici, Simona; Bolfa, Pompei; Catoi, Cornel; Baldea, Ioana; Bolojan, Laura; Olteanu, Diana; Muresan, Adriana; Postescu, I D

2011-11-03

The study investigated the protective activity of red grape seeds (Vitis vinifera L, Burgund Mare variety) (BM) extracts in vivo on multiple doses of ultraviolet radiation (UV)-B-induced deleterious effects in SKH-1 mice skin. Eighty 8-weeks-old female SKH-1 mice were divided into 8 groups: control, vehicle, UV-B irradiated, vehicle+UV-B irradiated, BM 2.5mg polyphenols (PF)/cm(2)+UV-B irradiated, BM 4 mg PF/cm(2)+UV-B irradiated, UV-B+BM 2.5mg PF/cm(2), UV-B+BM 4 mg PF/cm(2). The extract was applied topically before or after each UV-B exposure (240 mJ/cm(2)), for 10 days consecutively. The antioxidant activity of BM extract is higher than gallic acid (k(BM)=0.017, k(gallic acid)=0.013). Multiple doses of UV-B generated the formation of cyclobutane pyrimidine dimers (CPDs) and sunburn cells, increased glutathione peroxidase (GPx) and catalase (CAT) activities respectively glutathione (GSH) and IL-1β levels in skin. In group treated with 2.5mg PF/cm(2) before UV-B irradiation BM extract inhibited UV-B-induced sunburn cells, restored the superoxide dismutase (MnSOD) activity, increased insignificantly CAT and GPx activities and reduced IL-1β level. The BM 4.0 mg PF/cm(2) treatment decreased GSH level and reduced the percentage of CPDs positive cells in skin. Both doses of BM extract administered after UV-B irradiation increased the MnSOD and GPx activities and reduced the formation of sunburn cells in skin. Our results suggest that BM extract might be a potential chemo-preventive candidate in reducing the oxidative stress and apoptosis induced by multiple doses of UV-B in skin. Copyright © 2011 Elsevier B.V. All rights reserved.

Hypersensitivity of skin fibroblasts from basal cell nevus syndrome patients to killing by ultraviolet B but not by ultraviolet C radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Applegate, L.A.; Goldberg, L.H.; Ley, R.D.

Basal cell nevus syndrome (BCNS) is an autosomal dominant genetic disorder in which the afflicted individuals are extremely susceptible to sunlight-induced skin cancers, particularly basal cell carcinomas. However, the cellular and molecular basis for BCNS is unknown. To ascertain whether there is any relationship between genetic predisposition to skin cancer and increased sensitivity of somatic cells from BCNS patients to killing by UV radiation, we exposed skin fibroblasts established from unexposed skin biopsies of several BCNS and age- and sex-matched normal individuals to either UV-B (280-320 nm) or UV-C (254 nm) radiation and determined their survival. The results indicated thatmore » skin fibroblasts from BCNS patients were hypersensitive to killing by UV-B but not UV-C radiation as compared to skin fibroblasts from normal individuals. DNA repair studies indicated that the increased sensitivity of BCNS skin fibroblasts to killing by UV-B radiation was not due to a defect in the excision repair of pyrimidine dimers. These results indicate that there is an association between hypersensitivity of somatic cells to killing by UV-B radiation and the genetic predisposition to skin cancer in BCNS patients. In addition, these results suggest that DNA lesions (and repair processes) other than the pyrimidine dimer are also involved in the pathogenesis of sunlight-induced skin cancers in BCNS patients. More important, the UV-B sensitivity assay described here may be used as a diagnostic tool to identify presymptomatic individuals with BCNS.« less

Scutellaria radix Extract as a Natural UV Protectant for Human Skin.

PubMed

Seok, Jin Kyung; Kwak, Jun Yup; Choi, Go Woon; An, Sang Mi; Kwak, Jae-Hoon; Seo, Hyeong-Ho; Suh, Hwa-Jin; Boo, Yong Chool

2016-03-01

Ultraviolet (UV) radiation induces oxidative injury and inflammation in human skin. Scutellaria radix (SR, the root of Scutellaria baicalensis Georgi) contains flavonoids with high UV absorptivity and antioxidant properties. The purpose of this study was to examine the potential use of SR extract as an additive in cosmetic products for UV protection. SR extract and its butanol (BuOH) fraction strongly absorbed UV radiation and displayed free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radials and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals. They also attenuated the UV-induced death of HaCaT cells. Sunscreen creams, with or without supplementation of SR extract BuOH fraction, were tested in vivo in human trials to evaluate potential skin irritation and determine the sun protection factor (SPF). Both sunscreen creams induced no skin irritation. A sunscreen cream containing 24% ZnO showed an SPF value of 17.8, and it increased to 22.7 when supplemented with 5% SR extract BuOH fraction. This study suggests that SR-derived materials are useful as safe cosmetic additives that provide UV protection. Copyright © 2015 John Wiley & Sons, Ltd.

A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin.

PubMed

Mujahid, Nisma; Liang, Yanke; Murakami, Ryo; Choi, Hwan Geun; Dobry, Allison S; Wang, Jinhua; Suita, Yusuke; Weng, Qing Yu; Allouche, Jennifer; Kemeny, Lajos V; Hermann, Andrea L; Roider, Elisabeth M; Gray, Nathanael S; Fisher, David E

2017-06-13

The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in "redhaired" Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The protective effect of 18β-Glycyrrhetinic acid against UV irradiation induced photoaging in mice.

PubMed

Kong, Song-Zhi; Chen, Hai-Ming; Yu, Xiu-Ting; Zhang, Xie; Feng, Xue-Xuan; Kang, Xin-Huang; Li, Wen-Jie; Huang, Na; Luo, Hui; Su, Zi-Ren

2015-01-01

It has been confirmed that repeated exposure of skin to ultraviolet (UV) radiation results in cutaneous oxidative stress and inflammation, which act in concert to cause premature skin aging, well known as photoaging. 18β-Glycyrrhetinic acid (GA), widely used to treat various tissue inflammations, is the main active component of licorice root, and has also been shown to possess favorable anti-oxidative property and modulating immunity function. In the present study, we investigated the potential protective effect of GA on UV-induced skin photoaging in a mouse model. During the experimental period of ten consecutive weeks, the dorsal depilated skin of mice was treated with topical GA for 2 hours prior to UV irradiation. The results showed that GA pretreatment significantly alleviated the macroscopic and histopathological damages in mice skin caused by UV. Meanwhile, the data also indicated that GA markedly up-regulated the activities of the antioxidant enzymes (SOD, GSH-Px), and increased the content of skin collagen, while obviously decreased malonaldehyde level and inhibited high expressions of matrix metalloproteinase-1 (MMP-1) and -3 (MMP-3), as well as down-regulated the expression of inflammatory cytokines such as IL-6, TNF-α and IL-10. Taken together, these findings amply demonstrate that GA observably attenuates UV-induced skin photoaging mainly by virtue of its antioxidative and anti-inflammatory properties, as well as regulating the abnormal expression of MMP-1 and MMP-3. Copyright © 2014 Elsevier Inc. All rights reserved.

Inhibitory effect of flavonoids from citrus plants on Epstein-Barr virus activation and two-stage carcinogenesis of skin tumors.

PubMed

Iwase, Y; Takemura, Y; Ju-ichi, M; Ito, C; Furukawa, H; Kawaii, S; Yano, M; Mou, X Y; Takayasu, J; Tokuda, H; Nishino, H

2000-06-01

To search for possible anti-tumor promoters, thirteen flavones (1-13) obtained from the peel of Citrus plants were examined for their inhibitory effects on the Epstein-Barr virus early antigen (EBV-EA) activation by a short-term in vitro assay. Of these flavones, 3,5,6,7,8,3',4'-heptamethoxyflavone (HPT) (13) exhibited significant inhibitory effects on the EBV-EA activation induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, compound 13 exhibited remarkable inhibitory effects on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

Exposure to Non-Extreme Solar UV Daylight: Spectral Characterization, Effects on Skin and Photoprotection

PubMed Central

Marionnet, Claire; Tricaud, Caroline; Bernerd, Françoise

2014-01-01

The link between chronic sun exposure of human skin and harmful clinical consequences such as photo-aging and skin cancers is now indisputable. These effects are mostly due to ultraviolet (UV) rays (UVA, 320–400 nm and UVB, 280–320 nm). The UVA/UVB ratio can vary with latitude, season, hour, meteorology and ozone layer, leading to different exposure conditions. Zenithal sun exposure (for example on a beach around noon under a clear sky) can rapidly induce visible and well-characterized clinical consequences such as sunburn, predominantly induced by UVB. However, a limited part of the global population is exposed daily to such intense irradiance and until recently little attention has been paid to solar exposure that does not induce any short term clinical impact. This paper will review different studies on non-extreme daily UV exposures with: (1) the characterization and the definition of the standard UV daylight and its simulation in the laboratory; (2) description of the biological and clinical effects of such UV exposure in an in vitro reconstructed human skin model and in human skin in vivo, emphasizing the contribution of UVA rays and (3) analysis of photoprotection approaches dedicated to prevent the harmful impact of such UV exposure. PMID:25546388

Exposure to non-extreme solar UV daylight: spectral characterization, effects on skin and photoprotection.

PubMed

Marionnet, Claire; Tricaud, Caroline; Bernerd, Françoise

2014-12-23

The link between chronic sun exposure of human skin and harmful clinical consequences such as photo-aging and skin cancers is now indisputable. These effects are mostly due to ultraviolet (UV) rays (UVA, 320-400 nm and UVB, 280-320 nm). The UVA/UVB ratio can vary with latitude, season, hour, meteorology and ozone layer, leading to different exposure conditions. Zenithal sun exposure (for example on a beach around noon under a clear sky) can rapidly induce visible and well-characterized clinical consequences such as sunburn, predominantly induced by UVB. However, a limited part of the global population is exposed daily to such intense irradiance and until recently little attention has been paid to solar exposure that does not induce any short term clinical impact. This paper will review different studies on non-extreme daily UV exposures with: (1) the characterization and the definition of the standard UV daylight and its simulation in the laboratory; (2) description of the biological and clinical effects of such UV exposure in an in vitro reconstructed human skin model and in human skin in vivo, emphasizing the contribution of UVA rays and (3) analysis of photoprotection approaches dedicated to prevent the harmful impact of such UV exposure.

Towards standardization of UV eye protection: what can be learned from photodermatology?

PubMed

Krutmann, Jean; Béhar-Cohen, Francine; Baillet, Gilles; de Ayguavives, Tito; Ortega Garcia, Paula; Peña-García, Pablo; Remé, Charlotte; Wolffsohn, James

2014-01-01

While knowledge about standardization of skin protection against ultraviolet radiation (UVR) has progressed over the past few decades, there is no uniform and generally accepted standardized measurement for UV eye protection. The literature provides solid evidence that UV can induce considerable damage to structures of the eye. As well as damaging the eyelids and periorbital skin, chronic UV exposure may also affect the conjunctiva and lens. Clinically, this damage can manifest as skin cancer and premature skin ageing as well as the development of pterygia and premature cortical cataracts. Modern eye protection, used daily, offers the opportunity to prevent these adverse sequelae of lifelong UV exposure. A standardized, reliable and comprehensive label for consumers and professionals is currently lacking. In this review we (i) summarize the existing literature about UV radiation-induced damage to the eye and surrounding skin; (ii) review the recent technological advances in UV protection by means of lenses; (iii) review the definition of the Eye-Sun Protection Factor (E-SPF®), which describes the intrinsic UV protection properties of lenses and lens coating materials based on their capacity to absorb or reflect UV radiation; and (iv) propose a strategy for establishing the biological relevance of the E-SPF. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dumaz, N.; Drougard, C.; Sarasin, A.

1993-11-15

The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. The authors have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a goodmore » target for studying mutation spectra since there are >100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze >40 XP skin tumors (mainly basal and squamous cell carcinomas), the authors have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. All the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions. Sixty-one percent of these mutations were tandem CC [yields] TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. All the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidine-pyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.« less

The Immunologic Revolution: Photoimmunology

PubMed Central

Ullrich, Stephen E.; Byrne, Scott N.

2011-01-01

UV radiation targets the skin and is a primary cause of skin cancer (both melanoma and non-melanoma skin cancer). Exposure to UV also suppresses the immune response, and UV-induced immune suppression is a major risk factor for skin cancer induction. The efforts of Dermatologists and Cancer Biologists to understand how UV exposure suppresses the immune response and contributes to skin cancer induction led to the development of the sub-discipline we call photoimmunology. Advances in photoimmunology have generally paralleled advances in immunology. However, there are a number of examples where investigations into the mechanisms underlying UV-induced immune suppression reshaped our understanding of basic immunological concepts. Unconventional immune regulatory roles for Langerhans cells, mast cells, and NKT cells as well as the immune suppressive function of lipid mediators of inflammation and alarmins, are just some examples of how advances in immunodermatology have altered our understanding of basic immunology. In this anniversary issue celebrating 75 years of Cutaneous Science, we will provide examples of how concepts that grew out of efforts by Immunologists and Dermatologists to understand immune regulation by UV radiation impacted on immunology in general. PMID:22170491

Transcriptional regulation of ataxia-telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions.

PubMed

Beesetti, S; Mavuluri, J; Surabhi, R P; Oberyszyn, T M; Tober, K; Pitani, R S; Joseph, L D; Venkatraman, G; Rayala, S K

2017-11-02

Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia-telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.

Initiation-promotion skin carcinogenesis and immunological competence.

PubMed

Curtis, G L; Stenbäck, F; Ryan, W L

1975-10-01

The immune competence of mice during initiation-promotion skin carcinogenesis was determined by skin allograft rejection and lymphocyte mitogenesis. The carcinogen 7, 12-dimethylbenzanthracene inhibited the cellular immune competence of mice while lymphocytes from croton oil treated mice had enhanced PWM response. Chlorphenesin, a stimulator of cellular immunity, was found to inhibit tumorigenesis in initiation-promotion skin carcinogenesis when injected during promotion.

Epilobium angustifolium extract demonstrates multiple effects on dermal fibroblasts in vitro and skin photo-protection in vivo.

PubMed

Ruszová, Ema; Cheel, José; Pávek, Stanislav; Moravcová, Martina; Hermannová, Martina; Matějková, Ilona; Spilková, Jiřina; Velebný, Vladimír; Kubala, Lukáš

2013-09-01

Stress-induced fibroblast senescence is thought to contribute to skin aging. Ultraviolet light (UV) radiation is the most potent environmental risk factor in these processes. An Epilobium angustifolium (EA) extract was evaluated for its capacity to reverse the senescent response of normal human dermal fibroblasts (NHDF) in vitro and to exhibit skin photo-protection in vivo. The HPLC-UV-MS analysis of the EA preparation identified three major polyphenol groups: tannins (oenothein B), phenolic acids (gallic and chlorogenic acids) and flavonoids. EA extract increased the cell viability of senescent NHDF induced by serum deprivation. It diminished connective tissue growth factor and fibronectin gene expressions in senescent NHDF. Down-regulation of the UV-induced release of both matrix metalloproteinase-1 and -3 and the tissue inhibitor of matrix metalloproteinases-1 and -2, and also down-regulation of the gene expression of hyaluronidase 2 were observed in repeatedly UV-irradiated NHDF after EA extract treatment. Interestingly, EA extract diminished the down-regulation of sirtuin 1 dampened by UV-irradiation. The application of EA extract using a sub-irritating dose protected skin against UV-induced erythema formation in vivo. In summary, EA extract diminished stress-induced effects on NHDF, particularly on connective tissue growth factor, fibronectin and matrix metalloproteinases. These results collectively suggest that EA extract may possess anti-aging properties and that the EA polyphenols might account for these benefits.

Nucleotide Excision Repair and Vitamin D--Relevance for Skin Cancer Therapy.

PubMed

Pawlowska, Elzbieta; Wysokinski, Daniel; Blasiak, Janusz

2016-04-06

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.

Efficient intradermal delivery of superoxide dismutase using a combination of liposomes and iontophoresis for protection against UV-induced skin damage.

PubMed

Kigasawa, Kaoru; Miyashita, Moeko; Kajimoto, Kazuaki; Kanamura, Kiyoshi; Harashima, Hideyoshi; Kogure, Kentaro

2012-01-01

Superoxide dismutase (SOD) is a potent antioxidant agent that protects against UV-induced skin damage. However, its high molecular weight is a significant obstacle for efficient delivery into the skin through the stratum corneum and development of antioxidant activity. Recently, we developed a non-invasive transfollicular delivery system for macromolecules using a combination of liposomes and iontophoresis, that represents promising technology for enhancing transdermal administration of charged drugs (IJP, 403, 2011, Kajimoto et al.). In this study, in rats we attempted to apply this system to intradermal delivery of SOD for preventing UV-induced skin injury. SOD encapsulating in cationic liposomes was subjected to anodal iontophoresis. After iontophoretic treatment, the liposomes were diffused widely in the viable skin layer around hair follicles. In contrast, passive diffusion failed to transport liposomes efficiently into the skin. Iontophoretic delivery of liposomes encapsulating SOD caused a marked decrease in the production of oxidative products, such as malondialdehyde, hexanoyl lysine, and 8-hydroxi-2-deoxyguanosine, in UV-irradiated skin. These findings suggested that functional SOD can be delivered into the skin using a combination of iontophoresis and a liposomal system. In conclusion, we succeeded in developing an efficient intradermal SOD delivery system, that would be useful for delivery of other macromolecules.

Repair of cyclobutyl pyrimidine dimers in human skin: variability among normal humans in nucleotide excision and in photorepair.

PubMed

Sutherland, Betsy M; Hacham, Haim; Bennett, Paula; Sutherland, John C; Moran, Michael; Gange, R W

2002-06-01

Photoreactivation (PR) of cyclobutyl pyrimidine dimers (CPD) in human skin remains controversial. Recently Whitmore et al. (1) reported negative results of experiments using two photorepair light (PRL) sources on UV-irradiated skin of volunteers. However, their PRL sources induced substantial levels of dimers in skin, suggesting that the additional dimers formed could have obscured PR. We met a similar problem of dimer induction by a PRL source. We designed and validated a PRL source of sufficient intensity to catalyse PR, but that did not induce CPD, and used it to measure photorepair in human skin. Using a solar simulator filtered with three types of UV-filters, we found significant dimer formation in skin, quantified by number average length analysis using electrophoretic gels of isolated skin DNA. To prevent scattered UV from reaching the skin, we interposed shields between the filters and skin, and showed that the UV-filtered/shielded solar simulator system did not induce damage in isolated DNA or in human skin. We exposed skin of seven healthy human volunteers to 302 nm radiation, then to the improved PRL source (control skin areas were kept in the dark for measurement of excision repair). Using a high intensity PRL source that did not induce dimers in skin, we found that three of seven subjects carried out rapid photorepair of dimers; two carried out moderate or slow dimer photorepair, and three did not show detectable photorepair. Excision repair was similarly variable in these volunteers. Subjects with slower excision repair showed rapid photorepair, whereas those with rapid excision generally showed little or no photoreactivation.

UV exposure modulates hemidesmosome plasticity, contributing to long-term pigmentation in human skin

PubMed Central

Coelho, Sergio G.; Valencia, Julio C.; Yin, Lanlan; Smuda, Christoph; Mahns, Andre; Kolbe, Ludger; Miller, Sharon A.; Beer, Janusz Z.; Zhang, Guofeng; Tuma, Pamela L.; Hearing, Vincent J.

2014-01-01

Human skin color, i.e. pigmentation, differs widely among individuals as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals UV-induced pigmentation persists for months to years in a phenomenon termed long-lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, e.g. solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV-induced molecular changes may persist in individuals with LLP, clinical specimens from non-sunburn-inducing repeated UV exposures (UVA, UVB or UVA+UVB) at 4 months post-exposure (short-term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from 6 healthy individuals (3 LLP+ and 3 LLP-) followed for more than 9 months (long-term LLP) who initially received a single sunburn-inducing UVA+UVB exposure. The results support a UV-induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighboring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin α6β4 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal-dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long-term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin color. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP. PMID:25488118

UV exposure modulates hemidesmosome plasticity, contributing to long-term pigmentation in human skin.

PubMed

Coelho, Sergio G; Valencia, Julio C; Yin, Lanlan; Smuda, Christoph; Mahns, Andre; Kolbe, Ludger; Miller, Sharon A; Beer, Janusz Z; Zhang, Guofeng; Tuma, Pamela L; Hearing, Vincent J

2015-05-01

Human skin colour, ie pigmentation, differs widely among individuals, as do their responses to various types of ultraviolet radiation (UV) and their risks of skin cancer. In some individuals, UV-induced pigmentation persists for months to years in a phenomenon termed long-lasting pigmentation (LLP). It is unclear whether LLP is an indicator of potential risk for skin cancer. LLP seems to have similar features to other forms of hyperpigmentation, eg solar lentigines or age spots, which are clinical markers of photodamage and risk factors for precancerous lesions. To investigate what UV-induced molecular changes may persist in individuals with LLP, clinical specimens from non-sunburn-inducing repeated UV exposures (UVA, UVB or UVA + UVB) at 4 months post-exposure (short-term LLP) were evaluated by microarray analysis and dataset mining. Validated targets were further evaluated in clinical specimens from six healthy individuals (three LLP+ and three LLP-) followed for more than 9 months (long-term LLP) who initially received a single sunburn-inducing UVA + UVB exposure. The results support a UV-induced hyperpigmentation model in which basal keratinocytes have an impaired ability to remove melanin that leads to a compensatory mechanism by neighbouring keratinocytes with increased proliferative capacity to maintain skin homeostasis. The attenuated expression of SOX7 and other hemidesmosomal components (integrin α6β4 and plectin) leads to increased melanosome uptake by keratinocytes and points to a spatial regulation within the epidermis. The reduced density of hemidesmosomes provides supporting evidence for plasticity at the epidermal-dermal junction. Altered hemidesmosome plasticity, and the sustained nature of LLP, may be mediated by the role of SOX7 in basal keratinocytes. The long-term sustained subtle changes detected are modest, but sufficient to create dramatic visual differences in skin colour. These results suggest that the hyperpigmentation phenomenon leading to increased interdigitation develops in order to maintain normal skin homeostasis in individuals with LLP. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Elimination of deleterious effects of DMBA-induced skin carcinogenesis in mice by Syzygium cumini seed extract.

PubMed

Parmar, Jyoti; Sharma, Priyanka; Verma, Preeti; Sharma, Priyanka; Goyal, Pradeep K

2011-09-01

The inhibition of tumor incidence by hydro-alcoholic extract of S.cumini seed was evaluated in mice on two stage process of skin carcinogenesis induced by single application of 7, 12-dimethyl benz(a)anthracene (100 µg/100µl of acetone), and 2 weeks later promoted by repeated application of croton oil (1% acetone/thrice in a week) till the end of the experiment (i.e. 16 weeks). Oral administration of extract at a dose of 250mg/kg b.wt./day at the peri-initiational stage (i.e. 7 days before and 7 days after DMBA application), promotional stage (i.e. from the time of croton oil application) and at both the stages (i.e. 7 days prior to DMBA application & continued till the end of experiment) to the mice, recorded a significant reduction in tumor incidence to 37.5, 50 & 25% respectively in comparison to the carcinogen treated control, where tumor incidence was found as 100%. Tumor yield and Tumor burden were also significantly reduced by SCE. Similarly, the cumulative number of papillomas after 16 weeks was 68 in the control group, which was reduced to 15, 21 & 8 in the animals treated with the SCE continuously at peri-, post- and peri- & post- initiation stage respectively. A significant impairment was noticed in the levels of reduced glutathione, superoxide dismutase, catalase & protein and enhancement in LPO in liver and skin of carcinogen treated control mice as compared with vehicle treated mice. All such parameters were returned to near normal value by administration of SCE to DMBA treated mice. These results suggest a possible chemopreventive property of S.cumini against DMBA induced skin carcinogenesis in mice.

Chemoprevention of skin cancer by grape constituent resveratrol: relevance to human disease?

PubMed

Aziz, Moammir Hasan; Reagan-Shaw, Shannon; Wu, Jianqiang; Longley, B Jack; Ahmad, Nihal

2005-07-01

According to the World Cancer Report, skin cancer constitutes approximately 30% of all newly diagnosed cancers in the world, and solar ultraviolet (UV) radiation (particularly, its UVB component; 290-320 nm) is an established cause of approximately 90% of skin cancers. The available options have proven to be inadequate for the management of skin cancers. Therefore, there is an urgent need to develop mechanism-based novel approaches for prevention/therapy of skin cancer. In this study, we evaluated the chemopreventive effects of resveratrol against UVB radiation-mediated skin tumorigenesis in the SKH-1 hairless mouse model. For our studies, we used a UVB initiation-promotion protocol in which the control mice were subjected to chronic UVB exposure (180 mJ/cm2, twice weekly, for 28 weeks). The experimental animals received either a pretreatment (30 min before each UVB) or post-treatment (5 min after UVB) of resveratrol (25 or 50 micro mole/0.2 ml acetone/mouse). The mice were followed for skin tumorigenesis and were killed at 24 h after the last UVB exposure, for further studies. The topical application of skin with resveratrol (both pre- and post- treatment) resulted in a highly significant 1) inhibition in tumor incidence, and 2) delay in the onset of tumorigenesis. Interestingly, the post-treatment of resveratrol was found to impart equal protection than the pretreatment; suggesting that resveratrol-mediated responses may not be sunscreen effects. Because Survivin is a critical regulator of survival/death of cells, and its overexpression has been implicated in several cancers, we evaluated its involvement in chemoprevention of UVB-mediated skin carcinogenesis by resveratrol. Our data demonstrated a significant 1) up-regulation of Survivin (both at protein- and mRNA- levels), 2) up-regulation of phospho-Survivin protein, and 3) down-regulation of proapoptotic Smac/DIABLO protein in skin tumors; whereas treatment with resveratrol resulted in the attenuation of these responses. Our study also suggests that resveratrol enhanced apoptosis in UVB-exposure-mediated skin tumors. Our study, for the first time, demonstrated that 1) resveratrol imparts strong chemopreventive effects against UVB exposure-mediated skin carcinogenesis (relevant to human skin cancers), and 2) the chemopreventive effects of resveratrol may, at least in part, be mediated via modulations in Survivin and other associated events. On the basis of our work, it is conceivable to design resveratrol-containing emollient or patch, as well as sunscreen and skin-care products for prevention of skin cancer and other conditions, which are believed to be caused by UV radiation.

[Effect of long-wave ultraviolet light (UV-A) and medium-wave ultraviolet rays (UV-B) on human skin. Critical comparison].

PubMed

Raab, W

1980-04-15

When discussing the effects of ultraviolet radiation on human skin, one should carefully distinguish between the long wave ultraviolet light (UV-A) and the short wave radiations (UV-B and UV-C). Ultraviolet A induces immediate pigmentation but, if high energies are applied, a permanent pigmentation is elicited. This type of ultraviolet A-induced pigmentation has been called "spontaneous" pigmentation as no erythematous reaction is necessary to induce or accelerate melanine formation. Ultraviolet B provokes erythema and consecutive pigmentation. Upon chronic exposure, ultraviolet B causes the wellknown actinic damage of the skin and even provokes carcinoma. With exposures to the sunlight (global radiation), one should be most careful. The public must be informed extensively about the dangers of excessive sunbaths. The use of artificial "suns" with spectra between 260 and 400 nm is limited as it may cause the same type of damage as the global radiation. An exact schedule for use of artificial lamps is strongly recommended. After one cycle of exposures, an interruption is necessary until the next cycle of irradiations may start. Upon continual use for tanning of the skin, artificial lamps may provoke irreversible damage of the skin. Radiation sources with emission spectra of wavelengths between 315 and 400 nm exclusively are well suited for the induction of skin pigmentation (cosmetic use). Potent radiation such as UVASUN systems provoke a "pleasant" permanent pigmentation after exposures for less than one hour. The use of ultraviolet A (UV-A) does not carry any risk for the human skin.

Milk phospholipid's protective effects against UV damage in skin equivalent models

NASA Astrophysics Data System (ADS)

Dargitz, Carl; Russell, Ashley; Bingham, Michael; Achay, Zyra; Jimenez-Flores, Rafael; Laiho, Lily H.

2012-03-01

Exposure of skin tissue to UV radiation has been shown to cause DNA photodamage. If this damaged DNA is allowed to replicate, carcinogenesis may occur. DNA damage is prevented from being passed on to daughter cells by upregulation of the protein p21. p21 halts the cells cycle allowing the cell to undergo apoptosis, or repair its DNA before replication. Previous work suggested that milk phospholipids may possess protective properties against UV damage. In this study, we observed cell morphology, cell apoptosis, and p21 expression in tissue engineered epidermis through the use of Hematoxylin and Eosin staining, confocal microscopy, and western blot respectively. Tissues were divided into four treatment groups including: a control group with no UV and no milk phospholipid treatment, a group exposed to UV alone, a group incubated with milk phospholipids alone, and a group treated with milk phospholipids and UV. All groups were incubated for twenty-four hours after treatment. Tissues were then fixed, processed, and embedded in paraffin. Performing western blots resulted in visible p21 bands for the UV group only, implying that in every other group, p21 expression was lesser. Numbers of apoptotic cells were determined by observing the tissues treated with Hoechst dye under a confocal microscope, and counting the number of apoptotic and total cells to obtain a percentage of apoptotic cells. We found a decrease in apoptotic cells in tissues treated with milk phospholipids and UV compared to tissues exposed to UV alone. Collectively, these results suggest that milk phospholipids protect cell DNA from damage incurred from UV light.

Skin β-endorphin mediates addiction to UV light.

PubMed

Fell, Gillian L; Robinson, Kathleen C; Mao, Jianren; Woolf, Clifford J; Fisher, David E

2014-06-19

UV light is an established carcinogen, yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize proopiomelanocortin (POMC) that is processed to melanocyte-stimulating hormone, inducing tanning. We show that, in rodents, another POMC-derived peptide, β-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in β-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. Although primordial UV addiction, mediated by the hedonic action of β-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in humans. Copyright © 2014 Elsevier Inc. All rights reserved.

[Indoor tanning: motivations and beliefs among users and non-users in the population of Lille (Northern France)].

PubMed

Scalbert, C; Grenier, M; Maire, C; Cottencin, O; Bonnevalle, A; Behal, H; Duhamel, A; Glantenet, R; Mortier, L

2015-01-01

Uncontrolled use of tanning beds is a major public health problem. The role of UV in skin carcinogenesis has in fact been clearly demonstrated. The main purpose of the study was to assess the motivations and beliefs of the population concerning the use of indoor tanning. The secondary objectives were to compare the knowledge of users and non-users and to screen for addiction criteria among users. This was a transversal descriptive study conducted between April and June 2013 in Lille town center. The motivations of the participants were determined using a multiple-choice questionnaire. A Likert scale was used to assess beliefs and an m-CAGE questionnaire was used to screen for addiction. Of the 200 respondents, 30% (n=60) had used tanning beds in a non-medical setting. The median age of first use was 23 years (15-59). 11.7% of respondents had started before the authorised age of 18 years. "To prepare the skin for exposure to the sun" was the main reason given (68.3%) for use of tanning beds. The population was aware that use of such apparatus favours onset of skin cancer and ageing of the skin. Users were more convinced than non-users that UV cabins "prepare the skin for exposure to the sun" (75% vs. 49.6%, P=0.0009) and that they "favour skin cancer" (56.9% against 36.2%, P=0.0444). Addictive behaviour was detected in 3.3% (2/60) of users. Users are aware of the carcinogenic risk of UV cabins but expose themselves to such risk, as they believe it prepares their skin for sun exposure. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy

PubMed Central

Lee, Chih-Hung; Wu, Shi-Bei; Hong, Chien-Hui; Yu, Hsin-Su; Wei, Yau-Huei

2013-01-01

The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases. PMID:23519108

Hope and challenge: the importance of ultraviolet (UV) radiation for cutaneous vitamin D synthesis and skin cancer.

PubMed

Reichrath, Jörg; Reichrath, Sandra

2012-01-01

Abstract Solar ultraviolet (UV)-radiation is the most important environmental risk factor for the development of non-melanoma skin cancer (most importantly basal and squamous cell carcinomas), that represent the most common malignancies in Caucasian populations. To prevent these malignancies, public health campaigns were developed to improve the awareness of the general population of the role of UV-radiation. The requirements of vitamin D is mainly achieved by UV-B-induced cutaneous photosynthesis, and the vitamin D-mediated positive effects of UV-radiation were not always adequately considered in these campaigns; a strict "no sun policy" might lead to vitamin D-deficiency. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases has been convincingly demonstrated. It is crucial that guidelines for UV-exposure (e.g. in skin cancer prevention campaigns) consider these facts and give recommendations how to prevent vitamin D-deficiency. In this review, we analyze the present literature to help developing well-balanced guidelines on UV-protection that ensure an adequate vitamin D-status without increasing the risk to develop UV-induced skin cancer.

Tomatoes protect against development of UV-induced keratinocyte carcinoma via metabolomic alterations.

PubMed

Cooperstone, Jessica L; Tober, Kathleen L; Riedl, Ken M; Teegarden, Matthew D; Cichon, Morgan J; Francis, David M; Schwartz, Steven J; Oberyszyn, Tatiana M

2017-07-11

Prolonged tomato consumption can mitigate ultraviolet (UV) light induced sunburn via unknown mechanisms. Dietary carotenoids distributed to skin are hypothesized to protect skin against UV-induced damage, although other phytochemicals may play a role. We hypothesize that tomato consumption would protect against skin cancer. SKH-1 hairless and immunocompetent mice (n = 180) were fed AIN-93G or AIN-93G + 10% tangerine or red tomato powder for 35 weeks. From weeks 11-20, mice (n = 120) were exposed to 2240 J/m 2 UV-B light, 3x/week, and tumors were tracked weekly. Control mice were fed the same diets but not exposed to UV. Tumor number was significantly lower in male mice consuming red tomato diets (1.73 ± 0.50, P = 0.015) or pooled tomato diets (2.03 ± 0.45, P = 0.017) compared to controls (4.04 ± 0.65). Carotenoid levels in plasma and skin were quantitated, with total lycopene higher in skin of tangerine fed animals despite a lower dose. Metabolomic analyses elucidated compounds derived from tomato glycoalkaloids (including tomatidine and hydroxylated-tomatidine) as significantly different metabolites in skin after tomato exposure. Here, we describe that tomato consumption can modulate risk for keratinocyte carcinomas; however, the role of the newly identified specific phytochemicals possibly responsible for this action require further investigation.

Wild chrysanthemum extract prevents UVB radiation-induced acute cell death and photoaging.

PubMed

Sun, Sujiao; Jiang, Ping; Su, Weiting; Xiang, Yang; Li, Jian; Zeng, Lin; Yang, Shuangjuan

2016-03-01

Wild chrysanthemum (Chrysanthemum indicum L.) is traditionally used in folk medicine as an anti-inflammatory agent. It is also used in the southwest plateau region of China to prevent ultraviolet-induced skin damage. However, the role and mechanism by which wild chrysanthemum prevents UV-induced skin damage and photoaging have never been investigated in vitro. In the present study, we found that aqueous extracts from wild chrysanthemum strongly reduced high-dose UVB-induced acute cell death of human immortalized keratinocytic HaCat cells. Wild chrysanthemum extract was also demonstrated to reduce low-dose UVB-induced expression of the photoaging-related matrix metalloproteinases MMP-2 and MMP-9. The ROS level elevated by UVB irradiation was strongly attenuated by wild chrysanthemum extract. Further study revealed that wild chrysanthemum extract reduced UVB-triggered ERK1/2 and p38 MAPK phosphorylation and their protective role, which is partially dependent on inhibiting p38 activation. These results suggest that wild chrysanthemum extract can protect the skin from UVB-induced acute skin damage and photoaging by reducing the intracellular reactive oxygen species (ROS) level and inhibiting p38 MAPK phosphorylation. The present study confirmed the protective role of wild chrysanthemum against UV-induced skin disorders in vitro and indicated the possible mechanism. Further study to identify the active components in wild chrysanthemum extract would be useful for developing new drugs for preventing and treating skin diseases, including skin cancer and photoaging, induced by UV irradiation.

UV radiation-induced skin aging in hairless mice is effectively prevented by oral intake of sea buckthorn (Hippophae rhamnoides L.) fruit blend for 6 weeks through MMP suppression and increase of SOD activity.

PubMed

Hwang, In Sik; Kim, Ji Eun; Choi, Sun Il; Lee, Hye Ryun; Lee, Young Ju; Jang, Min Ju; Son, Hong Ju; Lee, Hee Seob; Oh, Chung Hun; Kim, Bae Hwan; Lee, Sang Hak; Hwang, Dae Youn

2012-08-01

Oxidative stress and oxidative photodamage induced by UV radiation can cause serious skin damage that is characterized by wrinkling, roughness, laxity and pigmentation. The effects of a sea buckthorn (Hippophae rhamnoides L.) fruit blend (SFB) containing sea buckthorn fruit extract, blueberry extract and collagen on UV-induced skin aging were examined by treating hairless mice for 6 weeks with UV irradiation and SFB administered orally. The effects of SFB were measured in the skin of these mice by phenotypical and histological analysis and western blotting. According to wrinkle formation analysis, the oral intake of SFB induced a decrease in wrinkle formation in the damaged skin of UV-irradiated mice. The thickness of the epidermis and dermis in the vitamin extracts (Vit)- and SFB-treated group was lower than that in the vehicle-treated group, but the group treated with SFB50 was the most effective group. The mice treated with the Vit- or SFB solution maintained a normal moisture content through the inhibition of transdermal water loss (TEWL) and an increase in skin moisture content. Furthermore, the levels of matrix metalloproteinase (MMP) and collagen protein expression were assessed in five groups to examine the mechanisms underlying the effects of SFB oral intake. The application of SFB induced a decrease in MMP-1 and -9 expression to the levels observed in the vehicle-treated group, but MMP-9 expression showed a much larger decrease than MMP-1. Furthermore, the expression of collagen-1 in the skin corresponded to MMP expression except for the SFB30-treated group, whereas the superoxide dismutase (SOD) activity was increased dramatically in the SFB50-treated group. These results suggest that SFB has potential as a protective and therapeutic drug candidate against skin aging that functions by regulating the moisture content, MMP expression levels and SOD activity.

Human papillomavirus 16 E5 oncogene contributes to two stages of skin carcinogenesis.

PubMed

Maufort, John P; Williams, Sybil M Genther; Pitot, Henry C; Lambert, Paul F

2007-07-01

High-risk human papillomaviruses (HPVs), which cause the vast majority of cervical cancer, other anogenital cancers, and a subset of head and neck squamous cell carcinomas, encode three oncogenes: E5, E6, and E7. To determine the oncogenic properties of HPV16 E5 in vivo, we previously generated K14E5 transgenic mice, in which expression of E5 was directed to the basal compartment of stratified squamous epithelia. In these mice, E5 induced epidermal hyperplasia and spontaneous skin tumors. In the current study, we determined how E5 contributes to tumor formation in the skin using a multistage model for skin carcinogenesis that specifies the role of genes in three stages: initiation, promotion, and malignant progression. Both initiation and promotion are required steps for papilloma formation. K14E5 mice treated with the initiating agent 7,12-dimethylbenz(a)anthracene (DMBA) developed more papillomas than like-treated nontransgenic mice, whereas neither K14E5 nor nontransgenic mice treated with the promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) developed papillomas. K14E5 mice treated with both DMBA and TPA to induce large numbers of papillomas had a higher incidence and earlier onset of carcinoma progression compared with like-treated nontransgenic mice. Thus, HPV16 E5 contributes to two stages of skin carcinogenesis: promotion and progression. The progressive neoplastic disease in K14E5 mice differed from that in nontransgenic mice in that benign tumors converted from exophytic to endophytic papillomas before progressing to carcinomas. Initial genetic and immunohistopathologic analyses did not determine the underlying basis for this distinct morphology, which correlates with a highly penetrant neoplastic phenotype.

Xeroderma Pigmentosum - Facts and Perspectives.

PubMed

Lehmann, Janin; Seebode, Christina; Martens, Marie Christine; Emmert, Steffen

2018-02-01

Ultraviolet (UV)-induced DNA lesions are almost exclusively removed by the nucleotide excision repair (NER) pathway, which is essential for prevention of skin cancer development. Patients with xeroderma pigmentosum (XP) are extremely sun sensitive due to a genetic defect in components of the NER cascade. They present with first signs of premature skin aging at an early age, with a considerably increased risk of developing UV-induced skin cancer. XP belongs to the group of DNA repair defective disorders that are mainly diagnosed in the clinic and in hindsight confirmed at the molecular level. Unfortunately, there are no causative treatment options for this rare, autosomal-recessive disorder, emphasizing the importance of an early diagnosis. Subsequently, UV-protective measures such as the reduction of exposure to environmental UV and regular skin cancer screenings should be undertaken to substantially improve prognosis as well as the disease course. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Molecular aspects of ultraviolet radiation-induced apoptosis in the skin.

PubMed

Chow, Jeffrey; Tron, Victor A

2005-12-01

Apoptosis, or programmed cell death, is an essential physiological process that controls cell numbers during physiological processes, and eliminates abnormal cells that can potentially harm an organism. This review summarizes our current state of knowledge of apoptosis induction in skin by UV radiation. A review of the literature was undertaken focusing on cell death in the skin secondary to UV radiation. It is evident that a number of apoptotic pathways, both intrinsic and extrinsic, are induced following exposure to damaging UV radiation. Although our understanding of the apoptotic processes is gradually increasing, many important aspects remain obscure. These include interconnections between pathways, wavelength-specific differences and cell type differences.

Dynamic maps of UV damage formation and repair for the human genome

PubMed Central

Hu, Jinchuan; Adebali, Ogun; Adar, Sheera; Sancar, Aziz

2017-01-01

Formation and repair of UV-induced DNA damage in human cells are affected by cellular context. To study factors influencing damage formation and repair genome-wide, we developed a highly sensitive single-nucleotide resolution damage mapping method [high-sensitivity damage sequencing (HS–Damage-seq)]. Damage maps of both cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] from UV-irradiated cellular and naked DNA revealed that the effect of transcription factor binding on bulky adducts formation varies, depending on the specific transcription factor, damage type, and strand. We also generated time-resolved UV damage maps of both CPDs and (6-4)PPs by HS–Damage-seq and compared them to the complementary repair maps of the human genome obtained by excision repair sequencing to gain insight into factors that affect UV-induced DNA damage and repair and ultimately UV carcinogenesis. The combination of the two methods revealed that, whereas UV-induced damage is virtually uniform throughout the genome, repair is affected by chromatin states, transcription, and transcription factor binding, in a manner that depends on the type of DNA damage. PMID:28607063

Dynamic maps of UV damage formation and repair for the human genome.

PubMed

Hu, Jinchuan; Adebali, Ogun; Adar, Sheera; Sancar, Aziz

2017-06-27

Formation and repair of UV-induced DNA damage in human cells are affected by cellular context. To study factors influencing damage formation and repair genome-wide, we developed a highly sensitive single-nucleotide resolution damage mapping method [high-sensitivity damage sequencing (HS-Damage-seq)]. Damage maps of both cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] from UV-irradiated cellular and naked DNA revealed that the effect of transcription factor binding on bulky adducts formation varies, depending on the specific transcription factor, damage type, and strand. We also generated time-resolved UV damage maps of both CPDs and (6-4)PPs by HS-Damage-seq and compared them to the complementary repair maps of the human genome obtained by excision repair sequencing to gain insight into factors that affect UV-induced DNA damage and repair and ultimately UV carcinogenesis. The combination of the two methods revealed that, whereas UV-induced damage is virtually uniform throughout the genome, repair is affected by chromatin states, transcription, and transcription factor binding, in a manner that depends on the type of DNA damage.

The simultaneous detection of mitochondrial DNA damage from sun-exposed skin of three whale species and its association with UV-induced microscopic lesions and apoptosis.

PubMed

Bowman, Amy; Martinez-Levasseur, Laura M; Acevedo-Whitehouse, Karina; Gendron, Diane; Birch-Machin, Mark A

2013-07-01

Due to life history and physiological constraints, cetaceans (whales) are unable to avoid prolonged exposure to external environmental insults, such as solar ultraviolet radiation (UV). The majority of studies on the effects of UV on skin are restricted to humans and laboratory animals, but it is important to develop tools to understand the effects of UV damage on large mammals such as whales, as these animals are long-lived and widely distributed, and can reflect the effects of UV across a large geographical range. We and others have used mitochondrial DNA (mtDNA) as a reliable marker of UV-induced damage particularly in human skin. UV-induced mtDNA strand breaks or lesions accumulate throughout the lifespan of an individual, thus constituting an excellent biomarker for cumulative exposure. Based on our previous studies in human skin, we have developed for the first time in the literature a quantitative real-time PCR methodology to detect and quantify mtDNA lesions in skin from sun-blistered whales. Furthermore the methodology allows for simultaneous detection of mtDNA damage in different species. Therefore using 44 epidermal mtDNA samples collected from 15 blue whales, 10 fin whales, and 19 sperm whales from the Gulf of California, Mexico, we quantified damage across 4.3 kilobases, a large region of the ~16,400 base pair whale mitochondrial genome. The results show a range of mtDNA damage in the skin of the three different whale species. This previously unreported observation was correlated with apoptotic damage and microscopic lesions, both of which are markers of UV-induced damage. As is the case in human studies, this suggests the potential use of mtDNA as a biomarker for measuring the effect of cumulative UV exposure in whales and may provide a platform to help understand the effects of changing global environmental conditions. Copyright © 2013 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.

How UV Light Touches the Brain and Endocrine System Through Skin, and Why.

PubMed

Slominski, Andrzej T; Zmijewski, Michal A; Plonka, Przemyslaw M; Szaflarski, Jerzy P; Paus, Ralf

2018-05-01

The skin, a self-regulating protective barrier organ, is empowered with sensory and computing capabilities to counteract the environmental stressors to maintain and restore disrupted cutaneous homeostasis. These complex functions are coordinated by a cutaneous neuro-endocrine system that also communicates in a bidirectional fashion with the central nervous, endocrine, and immune systems, all acting in concert to control body homeostasis. Although UV energy has played an important role in the origin and evolution of life, UV absorption by the skin not only triggers mechanisms that defend skin integrity and regulate global homeostasis but also induces skin pathology (e.g., cancer, aging, autoimmune responses). These effects are secondary to the transduction of UV electromagnetic energy into chemical, hormonal, and neural signals, defined by the nature of the chromophores and tissue compartments receiving specific UV wavelength. UV radiation can upregulate local neuroendocrine axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis. Similar effects are seen after exposure of the eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.

Solar ultraviolet irradiation induces decorin degradation in human skin likely via neutrophil elastase.

PubMed

Li, Yong; Xia, Wei; Liu, Ying; Remmer, Henriette A; Voorhees, John; Fisher, Gary J

2013-01-01

Exposure of human skin to solar ultraviolet (UV) irradiation induces matrix metalloproteinase-1 (MMP-1) activity, which degrades type I collagen fibrils. Type I collagen is the most abundant protein in skin and constitutes the majority of skin connective tissue (dermis). Degradation of collagen fibrils impairs the structure and function of skin that characterize skin aging. Decorin is the predominant proteoglycan in human dermis. In model systems, decorin binds to and protects type I collagen fibrils from proteolytic degradation by enzymes such as MMP-1. Little is known regarding alterations of decorin in response to UV irradiation. We found that solar-simulated UV irradiation of human skin in vivo stimulated substantial decorin degradation, with kinetics similar to infiltration of polymorphonuclear (PMN) cells. Proteases that were released from isolated PMN cells degraded decorin in vitro. A highly selective inhibitor of neutrophil elastase blocked decorin breakdown by proteases released from PMN cells. Furthermore, purified neutrophil elastase cleaved decorin in vitro and generated fragments with similar molecular weights as those resulting from protease activity released from PMN cells, and as observed in UV-irradiated human skin. Cleavage of decorin by neutrophil elastase significantly augmented fragmentation of type I collagen fibrils by MMP-1. Taken together, these data indicate that PMN cell proteases, especially neutrophil elastase, degrade decorin, and this degradation renders collagen fibrils more susceptible to MMP-1 cleavage. These data identify decorin degradation and neutrophil elastase as potential therapeutic targets for mitigating sun exposure-induced collagen fibril degradation in human skin.

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

PubMed

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.

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

PubMed Central

Stephan, Sonja; Braspenning-Wesch, Ilona; Mikulec, Julita; Niebler, Martina; Gröne, Hermann-Josef; Flechtenmacher, Christa; Akgül, Baki

2017-01-01

Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored—like in humans—Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC. PMID:29190285

Efficient topical delivery of chlorogenic acid by an oil-in-water microemulsion to protect skin against UV-induced damage.

PubMed

Kitagawa, Shuji; Yoshii, Kenta; Morita, Shin-ya; Teraoka, Reiko

2011-01-01

We examined the intradermal delivery of a hydrophilic polyphenol chlorogenic acid by in vitro study using excised guinea pig dorsal skin and Yucatan micropig skin. Skin accumulation as well as the solubility of chlorogenic acid in aqueous vehicles was much greater than for other polyphenols such as quercetin and genistein. However, since enhancement of skin delivery seemed to be necessary to exhibit its protective effects against oxidative damage of skin, we examined the effects of microemulsions as vehicles. Using microemulsions consisting of 150 mM NaCl solution, isopropyl myristate, polyoxyethylene sorbitan monooleate (Tween 80) and ethanol, skin accumulation as well as solubility of chlorogenic acid further increased. Enhancement effect of an oil-in-water (o/w-type) microemulsion was greater than that of a water-in-oil (w/o-type) microemulsion possibly due to the greater increase in solubility. This finding was quite different from previous findings on relatively hydrophobic polyphenols such as quercetin and genistein. Pretreatment of guinea pig dorsal skin with chlorogenic acid containing microemulsion gel prevented erythema formation induced by UV irradiation. These findings indicate the potential use of hydrophilic chlorogenic acid with o/w-type microemulsion as a vehicle to protect skin against UV-induced oxidative damage.

Different susceptibility of cells of porcine skin and internal organs to ultraviolet A-induced breaking of nuclear DNA.

PubMed

Brozyna, Anna; Chwirot, Barbara W

2005-01-01

There is a continuously growing interest in medical applications of ultraviolet radiation (UV-A and long-wavelength UV-B) especially for laser surgery, phototherapy and photodiagnostics of human internal organs. UV-B and UV-A radiation is potentially mutagenic, however, there has been very little information published to date concerning the significance of possible deleterious action of such photons on cells of internal tissues. The aim of this study is to compare the sensitivities of skin cells to those of internal organs upon exposure to UV-A. To assess this sensitivity we have determined the UV-A dose-dependent frequency of nuclear DNA breaks detected with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) technique. The materials for the study were macroscopic samples of porcine skin, colon and esophagus. The UV-A dose ranged from 0.1 to 1000 mJ/cm2, which is similar to doses received by cells in regions examined with laser-induced fluorescence or by cells surrounding areas subject to a laser ablation. To reduce the influence of DNA repair processes the tissue samples were kept at a low temperature during the irradiation and were deep frozen immediately after completing the irradiation procedure. The cells of the internal organs are much more susceptible to UV-A-induced breaking of DNA than the skin cells. The percentage fractions and the spatial distributions of the damaged cells and the characteristics of the UV-A dose dependence seem to vary by type of internal organ.

Whales Use Distinct Strategies to Counteract Solar Ultraviolet Radiation

PubMed Central

Martinez-Levasseur, Laura M.; Birch-Machin, Mark A.; Bowman, Amy; Gendron, Diane; Weatherhead, Elizabeth; Knell, Robert J.; Acevedo-Whitehouse, Karina

2013-01-01

A current threat to the marine ecosystem is the high level of solar ultraviolet radiation (UV). Large whales have recently been shown to suffer sun-induced skin damage from continuous UV exposure. Genotoxic consequences of such exposure remain unknown for these long-lived marine species, as does their capacity to counteract UV-induced insults. We show that UV exposure induces mitochondrial DNA damage in the skin of seasonally sympatric fin, sperm, and blue whales and that this damage accumulates with age. However, counteractive molecular mechanisms are markedly different between species. For example, sperm whales, a species that remains for long periods at the sea surface, activate genotoxic stress pathways in response to UV exposure whereas the paler blue whale relies on increased pigmentation as the season progresses. Our study also shows that whales can modulate their responses to fluctuating levels of UV, and that different evolutionary constraints may have shaped their response strategies. PMID:23989080

Dietary Milk Sphingomyelin Prevents Disruption of Skin Barrier Function in Hairless Mice after UV-B Irradiation.

PubMed

Oba, Chisato; Morifuji, Masashi; Ichikawa, Satomi; Ito, Kyoko; Kawahata, Keiko; Yamaji, Taketo; Asami, Yukio; Itou, Hiroyuki; Sugawara, Tatsuya

2015-01-01

Exposure to ultraviolet-B (UV-B) irradiation causes skin barrier defects. Based on earlier findings that milk phospholipids containing high amounts of sphingomyelin (SM) improved the water content of the stratum corneum (SC) in normal mice, here we investigated the effects of dietary milk SM on skin barrier defects induced by a single dose of UV-B irradiation in hairless mice. Nine week old hairless mice were orally administrated SM (146 mg/kg BW/day) for a total of ten days. After seven days of SM administration, the dorsal skin was exposed to a single dose of UV-B (20 mJ/cm2). Administration of SM significantly suppressed an increase in transepidermal water loss and a decrease in SC water content induced by UV-B irradiation. SM supplementation significantly maintained covalently-bound ω-hydroxy ceramide levels and down-regulated mRNA levels of acute inflammation-associated genes, including thymic stromal lymphopoietin, interleukin-1 beta, and interleukin-6. Furthermore, significantly higher levels of loricrin and transglutaminase-3 mRNA were observed in the SM group. Our study shows for the first time that dietary SM modulates epidermal structures, and can help prevent disruption of skin barrier function after UV-B irradiation.

A role for NF-κB–dependent gene transactivation in sunburn

PubMed Central

Abeyama, Kazuhiro; Eng, William; Jester, James V.; Vink, Arie A.; Edelbaum, Dale; Cockerell, Clay J.; Bergstresser, Paul R.; Takashima, Akira

2000-01-01

Exposure of skin to ultraviolet (UV) radiation is known to induce NF-κB activation, but the functional role for this pathway in UV-induced cutaneous inflammation remains uncertain. In this study, we examined whether experimentally induced sunburn reactions in mice could be prevented by blocking UV-induced, NF-κB–dependent gene transactivation with oligodeoxynucleotides (ODNs) containing the NF-κB cis element (NF-κB decoy ODNs). UV-induced secretion of IL-1, IL-6, TNF-α, and VEGF by skin-derived cell lines was inhibited by the decoy ODNs, but not by the scrambled control ODNs. Systemic or local injection of NF-κB decoy ODNs also inhibited cutaneous swelling responses to UV irradiation. Moreover, local UV-induced inflammatory changes (swelling, leukocyte infiltration, epidermal hyperplasia, and accumulation of proinflammatory cytokines) were all inhibited specifically by topically applied decoy ODNs. Importantly, these ODNs had no effect on alternative types of cutaneous inflammation caused by irritant or allergic chemicals. These results indicate that sunburn reactions culminate from inflammatory events that are triggered by UV-activated transcription of NF-κB target genes, rather than from nonspecific changes associated with tissue damage. PMID:10862790

Photodecomposition and Phototoxicity of Natural Retinoids

PubMed Central

Tolleson, William H.; Cherng, Shui-Hui; Xia, Qingsu; Boudreau, Mary; Yin, Jun Jie; Wamer, Wayne G.; Howard, Paul C.; Yu, Hongtao; Fu, Peter P.

2005-01-01

Sunlight is a known human carcinogen. Many cosmetics contain retinoid-based compounds, such as retinyl palmitate (RP), either to protect the skin or to stimulate skin responses that will correct skin damaged by sunlight. However, little is known about the photodecomposition of some retinoids and the toxicity of these retinoids and their sunlight-induced photodecomposition products on skin. Thus, studies are required to test whether topical application of retinoids enhances the phototoxicity and photocarcinogenicity of sunlight and UV light. Mechanistic studies are needed to provide insight into the disposition of retinoids in vitro and on the skin, and to test thoroughly whether genotoxic damage by UV-induced radicals may participate in any toxicity of topically applied retinoids in the presence of UV light. This paper reports the update information and our experimental results on photostability, photoreactions, and phototoxicity of the natural retinoids including retinol (ROH), retinal, retinoid acid (RA), retinyl acetate, and RP (Figure 1). PMID:16705812

Skin β-endorphin mediates addiction to ultraviolet light

PubMed Central

Fell, Gillian L.; Robinson, Kathleen C.; Mao, Jianren; Woolf, Clifford J.; Fisher, David E.

2014-01-01

SUMMARY Ultraviolet light is an established carcinogen yet evidence suggests that UV-seeking behavior has addictive features. Following UV exposure, epidermal keratinocytes synthesize Proopiomelanocortin that is processed to Melanocyte Stimulating Hormone, inducing tanning. We show that in rodents another POMC-derived peptide, β-endorphin, is coordinately synthesized in skin, elevating plasma levels after low-dose UV. Increases in pain-related thresholds are observed, and reversed by pharmacologic opioid antagonism. Opioid blockade also elicits withdrawal signs after chronic UV exposure. This effect was sufficient to guide operant behavioral choices to avoidance of opioid withdrawal (conditioned place aversion). These UV-induced nociceptive and behavioral effects were absent in β-endorphin knockout mice and in mice lacking p53-mediated POMC induction in epidermal keratinocytes. While primordial UV addiction, mediated by the hedonic action of β-endorphin and anhedonic effects of withdrawal, may theoretically have enhanced evolutionary vitamin D biosynthesis, it now may contribute to the relentless rise in skin cancer incidence in man. PMID:24949966

Differential regulation of a fibroblast growth factor-binding protein during skin carcinogenesis and wound healing.

PubMed

Kurtz, Andreas; Aigner, Achim; Cabal-Manzano, Rafael H; Butler, Robert E; Hood, Dozier R; Sessions, Roy B; Czubayko, Frank; Wellstein, Anton

2004-01-01

The initiation of premalignant lesions is associated with subtle cellular and gene expression changes. Here we describe a severe combined immunodeficiency mouse xenograft model with human adult skin and compare chemical carcinogenesis and wound healing. We focus on a secreted binding protein for fibroblast growth factors (FGF-BP) that enhances the activity of locally stored FGFs and is expressed at high levels in human epithelial cancers. Carcinogen treatment of murine skin induced papilloma within 6 weeks, whereas the human skin grafts displayed no obvious macroscopic alterations. Microscopic studies of the human skin, however, showed p53-positive keratinocytes in the epidermis, increased angiogenesis in the dermis of the treated skin, enhanced proliferation of keratinocytes in the basal layer, and an increase of FGF-BP protein and mRNA expression. In contrast, after surgical wounding of human skin grafts or of mouse skin, FGF-BP expression was upregulated within a few hours and returned to control levels after 2 days with wound closure. Enhanced motility of cultured keratinocytes and dermal fibroblasts by FGF-BP supports a role in wound healing. We conclude that adult human skin xenografts can be used to identify early molecular events during malignant transformation as well as transient changes during wound healing.

Acute UV irradiation increases heparan sulfate proteoglycan levels in human skin.

PubMed

Jung, Ji-Yong; Oh, Jang-Hee; Kim, Yeon Kyung; Shin, Mi Hee; Lee, Dayae; Chung, Jin Ho

2012-03-01

Glycosaminoglycans are important structural components in the skin and exist as various proteoglycan forms, except hyaluronic acid. Heparan sulfate (HS), one of the glycosaminoglycans, is composed of repeated disaccharide units, which are glucuronic acids linked to an N-acetyl-glucosamine or its sulfated forms. To investigate acute ultraviolet (UV)-induced changes of HS and HS proteoglycans (HSPGs), changes in levels of HS and several HSPGs in male human buttock skin were examined by immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR) after 2 minimal erythema doses (MED) of UV irradiation (each n = 4-7). HS staining revealed that 2 MED of UV irradiation increased its expression, and staining for perlecan, syndecan-1, syndecan-4, CD44v3, and CD44 showed that UV irradiation increased their protein levels. However, analysis by real-time qPCR showed that UV irradiation did not change mRNA levels of CD44 and agrin, and decreased perlecan and syndecan-4 mRNA levels, while increased syndecan-1 mRNA level. As HS-synthesizing or -degrading enzymes, exostosin-1 and heparanase mRNA levels were increased, but exostosin-2 was decreased by UV irradiation. UV-induced matrix metalloproteinase-1 expression was confirmed for proper experimental conditions. Acute UV irradiation increases HS and HSPG levels in human skin, but their increase may not be mediated through their transcriptional regulation.

Occupational skin cancer due to UV-irradiation--Analyses of notified cases as "virtually-certain" occupational disease in Germany between 2005 and 2011.

PubMed

Schmitt, Jochen; Diepgen, Thomas L

2014-06-01

UV-induced skin cancer is not yet included in the German ordinance on occupational diseases and can only be notified and recognized acknowledged as "virtually-certain" occupational disease. The objective of the study was to analyze notified and acknowledged cases of occupational skin cancer due to UV-irradiation in Germany between 2005 and 2011. All notified cases of occupational skin cancer due to UV-irradiation have been analyzed which have been registered by the German Statutory accident insurance as of May 2012 were analyzed. The data analyze was descriptive stratified annually for presenting time trends.Data analysis was descriptive, stratified by year to defect time trends. Notified cases have increased annually with a total of 548 registered cases of occupational skin cancer induced by UV-irradiation between 2005 and 2011, and 74 recognized acknowledged cases. In 56 cases the procedure was not yet finished. Squamous cell carcinoma (SCC) and in-situ squamous cell carcinoma (actinic keratosis, Bowen's disease) were most frequent and have been the most frequentlyobserved in 333 notified cases. and between 15.6 % and 24.9 % have been recognizedof cases with SCC and actinic keratosis were recognized, respectively. 184 patients with basal cell carcinoma were notified but only 6.5 % recognized acknowledged and only 3 cases with exclusive basal cell carcinoma. Out of 50 notified patients with Mmelanoma only one was recognizedacknowledged. The results are in good agreement with the proposal of the German Minister of labor to establish UV-induced skin cancer as a new occupational disease. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

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

PubMed

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.

The evolution of human skin coloration.

PubMed

Jablonski, N G; Chaplin, G

2000-07-01

Skin color is one of the most conspicuous ways in which humans vary and has been widely used to define human races. Here we present new evidence indicating that variations in skin color are adaptive, and are related to the regulation of ultraviolet (UV) radiation penetration in the integument and its direct and indirect effects on fitness. Using remotely sensed data on UV radiation levels, hypotheses concerning the distribution of the skin colors of indigenous peoples relative to UV levels were tested quantitatively in this study for the first time. The major results of this study are: (1) skin reflectance is strongly correlated with absolute latitude and UV radiation levels. The highest correlation between skin reflectance and UV levels was observed at 545 nm, near the absorption maximum for oxyhemoglobin, suggesting that the main role of melanin pigmentation in humans is regulation of the effects of UV radiation on the contents of cutaneous blood vessels located in the dermis. (2) Predicted skin reflectances deviated little from observed values. (3) In all populations for which skin reflectance data were available for males and females, females were found to be lighter skinned than males. (4) The clinal gradation of skin coloration observed among indigenous peoples is correlated with UV radiation levels and represents a compromise solution to the conflicting physiological requirements of photoprotection and vitamin D synthesis. The earliest members of the hominid lineage probably had a mostly unpigmented or lightly pigmented integument covered with dark black hair, similar to that of the modern chimpanzee. The evolution of a naked, darkly pigmented integument occurred early in the evolution of the genus Homo. A dark epidermis protected sweat glands from UV-induced injury, thus insuring the integrity of somatic thermoregulation. Of greater significance to individual reproductive success was that highly melanized skin protected against UV-induced photolysis of folate (Branda & Eaton, 1978, Science201, 625-626; Jablonski, 1992, Proc. Australas. Soc. Hum. Biol.5, 455-462, 1999, Med. Hypotheses52, 581-582), a metabolite essential for normal development of the embryonic neural tube (Bower & Stanley, 1989, The Medical Journal of Australia150, 613-619; Medical Research Council Vitamin Research Group, 1991, The Lancet338, 31-37) and spermatogenesis (Cosentino et al., 1990, Proc. Natn. Acad. Sci. U.S.A.87, 1431-1435; Mathur et al., 1977, Fertility Sterility28, 1356-1360).As hominids migrated outside of the tropics, varying degrees of depigmentation evolved in order to permit UVB-induced synthesis of previtamin D(3). The lighter color of female skin may be required to permit synthesis of the relatively higher amounts of vitamin D(3)necessary during pregnancy and lactation. Skin coloration in humans is adaptive and labile. Skin pigmentation levels have changed more than once in human evolution. Because of this, skin coloration is of no value in determining phylogenetic relationships among modern human groups. Copyright 2000 Academic Press.

Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes.

PubMed

Ferrucio, Bianca; Tiago, Manoela; Fannin, Richard D; Liu, Liwen; Gerrish, Kevin; Maria-Engler, Silvya Stuchi; Paules, Richard S; Barros, Silvia Berlanga de Moraes

2017-02-01

Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100μM) and solar radiation (375mJ/cm 2 ). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKN1A, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro protective effects of an aqueous extract of Clitoria ternatea L. flower against hydrogen peroxide-induced cytotoxicity and UV-induced mtDNA damage in human keratinocytes.

PubMed

Zakaria, N N A; Okello, E J; Howes, M-J; Birch-Machin, M A; Bowman, A

2018-06-01

The traditional practice of eating the flowers of Clitoria ternatea L. or drinking their infusion as herbal tea in some of the Asian countries is believed to promote a younger skin complexion and defend against skin aging. This study was conducted to investigate the protective effect of C. ternatea flower water extract (CTW) against hydrogen peroxide-induced cytotoxicity and ultraviolet (UV)-induced mitochondrial DNA (mtDNA) damage in human keratinocytes. The protective effect against hydrogen peroxide-induced cytotoxicity was determined by 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, and mtDNA damage induced by UV was determined by polymerase chain reaction. Preincubation of HaCaT with 100, 250, and 500 μg/ml CTW reduced cytotoxicity effects of H 2 O 2 compared with control (H 2 O 2 alone). CTW also significantly reduced mtDNA damage in UV-exposed HaCaT (p < .05). CTW was chemically-characterized using high resolution liquid chromatography-mass spectrometry. The main compounds detected were assigned as anthocyanins derived from delphinidin, including polyacylated ternatins, and flavonol glycosides derived from quercetin and kaempferol. These results demonstrated the protective effects of C. ternatea flower extracts that contain polyacylated anthocyanins and flavonol glycosides as major constituents, against H 2 O 2 and UV-induced oxidative stress on skin cells, and may provide some explanation for the putative traditional and cosmetic uses of C. ternatea flower against skin aging. Copyright © 2018 John Wiley & Sons, Ltd.

Effects of Hydroxydecine(®) (10-hydroxy-2-decenoic acid) on skin barrier structure and function in vitro and clinical efficacy in the treatment of UV-induced xerosis.

PubMed

Duplan, Hélène; Questel, Emmanuel; Hernandez-Pigeon, Hélène; Galliano, Marie Florence; Caruana, Antony; Ceruti, Isabelle; Ambonati, Marco; Mejean, Carine; Damour, Odile; Castex-Rizzi, Nathalie; Bessou-Touya, Sandrine; Schmitt, Anne-Marie

2011-01-01

10-Hydroxy-2-decenoic acid, a natural fatty acid only found in royal jelly, may be of value in correcting skin barrier dysfunction. We evaluated the activity of Hydroxydecine(®), its synthetic counterpart, in vitro on the regulation of epidermal differentiation markers, ex vivo on the inflammatory response and restoration of skin barrier function, and in vivo on UV-induced xerosis in healthy human volunteers. In cultured normal human keratinocytes, Hydroxydecine(®) induced involucrin, transglutaminase-1 and filaggrin protein production. In topically Hydroxydecine(®)-treated skin equivalents, immunohistochemical analysis revealed an increase in involucrin, transglutaminase-1 and filaggrin staining. In a model of thymic stromal lymphopoietin (TSLP)-induced inflamed epidermis, a Hydroxydecine(®)-containing emulsion inhibited TSLP release. In a model of inflammation and barrier impairment involving human skin explants maintained alive, Hydroxydecine(®) balm restored stratum corneum cohesion and significantly increased filaggrin expression, as shown by immunohistochemistry. It also decreased pro-inflammatory cytokine secretion (IL-4, IL-5 and IL-13). In healthy volunteers with UV-induced xerosis, the hydration index increased by +28.8% (p<0.01) and +60.4% (p<0.001) after 7 and 21 days of treatment with Hydroxydecine(®) cream, respectively. Hydroxydecine(®) thus proved its efficacy in activating keratinocyte differentiation processes in vitro, restoring skin barrier function and reducing inflammation ex vivo, and hydrating dry skin in vivo.

UV Induced Epigenetic Field Effect as a Target for Melanoma Therapy and Prevention

DTIC Science & Technology

2017-06-01

initiators or selected for during disease progression highlighting our lack in knowledge of the critical molecular targets in the initiation of UV...changes in the underlying molecular mechanisms of UV-induced melanoma. This would be the first evidence epigenetic alterations from UV-induced...i di id l i k d h l d fi li d i i15. SUBJECT TERMS Skin-cancer, melanoma, ultraviolet-radiation, epigenetics, methylation, genetics , melanomagenesis

Inhibition of mTOR by apigenin in UVB-irradiated keratinocytes: A new implication of skin cancer prevention.

PubMed

Bridgeman, Bryan B; Wang, Pu; Ye, Boping; Pelling, Jill C; Volpert, Olga V; Tong, Xin

2016-05-01

Ultraviolet B (UVB) radiation is the major environmental risk factor for developing skin cancer, the most common cancer worldwide, which is characterized by aberrant activation of Akt/mTOR (mammalian target of rapamycin). Importantly, the link between UV irradiation and mTOR signaling has not been fully established. Apigenin is a naturally occurring flavonoid that has been shown to inhibit UV-induced skin cancer. Previously, we have demonstrated that apigenin activates AMP-activated protein kinase (AMPK), which leads to suppression of basal mTOR activity in cultured keratinocytes. Here, we demonstrated that apigenin inhibited UVB-induced mTOR activation, cell proliferation and cell cycle progression in mouse skin and in mouse epidermal keratinocytes. Interestingly, UVB induced mTOR signaling via PI3K/Akt pathway, however, the inhibition of UVB-induced mTOR signaling by apigenin was not Akt-dependent. Instead, it was driven by AMPK activation. In addition, mTOR inhibition by apigenin in keratinocytes enhanced autophagy, which was responsible, at least in part, for the decreased proliferation in keratinocytes. In contrast, apigenin did not alter UVB-induced apoptosis. Taken together, our results indicate the important role of mTOR inhibition in UVB protection by apigenin, and provide a new target and strategy for better prevention of UV-induced skin cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

The Nrf2-inducers tanshinone I and dihydrotanshinone protect human skin cells and reconstructed human skin against solar simulated UV☆

PubMed Central

Tao, Shasha; Justiniano, Rebecca; Zhang, Donna D.; Wondrak, Georg T.

2013-01-01

Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis and photoaging, and an urgent need exists for improved strategies for skin photoprotection. The redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defense against environmental electrophilic insult, has recently emerged as an important determinant of cutaneous damage from solar UV, and the concept of pharmacological activation of Nrf2 has attracted considerable attention as a novel approach to skin photoprotection. In this study, we examined feasibility of using tanshinones, a novel class of phenanthrenequinone-based cytoprotective Nrf2 inducers derived from the medicinal plant Salvia miltiorrhiza, for protection of cultured human skin cells and reconstructed human skin against solar simulated UV. Using a dual luciferase reporter assay in human Hs27 dermal fibroblasts pronounced transcriptional activation of Nrf2 by four major tanshinones [tanshinone I (T-I), dihydrotanshinone (DHT), tanshinone IIA (T-II-A) and cryptotanshinone (CT)] was detected. In fibroblasts, the more potent tanshinones T-I and DHT caused a significant increase in Nrf2 protein half-life via blockage of ubiquitination, ultimately resulting in upregulated expression of cytoprotective Nrf2 target genes (GCLC, NQO1) with the elevation of cellular glutathione levels. Similar tanshinone-induced changes were also observed in HaCaT keratinocytes. T-I and DHT pretreatment caused significant suppression of skin cell death induced by solar simulated UV and riboflavin-sensitized UVA. Moreover, feasibility of tanshinone-based cutaneous photoprotection was tested employing a human skin reconstruct exposed to solar simulated UV (80 mJ/cm2 UVB; 1.53 J/cm2 UVA). The occurrence of markers of epidermal solar insult (cleaved procaspase 3, pycnotic nuclei, eosinophilic cytoplasm, acellular cavities) was significantly attenuated in DHT-treated reconstructs that displayed increased immunohistochemical staining for Nrf2 and γ-GCS together with the elevation of total glutathione levels. Taken together, our data suggest the feasibility of achieving tanshinone-based cutaneous Nrf2-activation and photoprotection. PMID:24273736

Quercitrin protects skin from UVB-induced oxidative damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, Yuanqin; Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY; Li, Wenqi

Exposure of the skin to ultraviolet B (UVB) radiation causes oxidative damage to skin, resulting in sunburn, photoaging, and skin cancer. It is generally believed that the skin damage induced by UV irradiation is a consequence of generation of reactive oxygen species (ROS). Recently, there is an increased interest in the use of natural products as chemopreventive agents for non-melanoma skin cancer (NMSC) due to their antioxidants and anti-inflammatory properties. Quercitrin, glycosylated form of quercetin, is the most common flavonoid in nature with antioxidant properties. The present study investigated the possible beneficial effects of quercitrin to inhibit UVB irradiation-induced oxidativemore » damage in vitro and in vivo. Our results showed that quercitrin decreased ROS generation induced by UVB irradiation in JB6 cells. Quercitrin restored catalase expression and GSH/GSSG ratio reduced by UVB exposure, two major antioxidant enzymes, leading to reductions of oxidative DNA damage and apoptosis and protection of the skin from inflammation caused by UVB exposure. The present study demonstrated that quercitrin functions as an antioxidant against UVB irradiation-induced oxidative damage to skin. - Highlights: • Oxidative stress plays a key role in UV-induced cell and tissue injuries. • Quercitrin decreases ROS generation and restores antioxidants irradiated by UVB. • Quercitrin reduces UVB-irradiated oxidative DNA damage, apoptosis, and inflammation. • Quercitrin functions as an antioxidant against UVB-induced skin injuries.« less

Towards a Better Understanding of the Effects of UV on Atlantic Walruses, Odobenus rosmarus rosmarus: A Study Combining Histological Data with Local Ecological Knowledge.

PubMed

Martinez-Levasseur, Laura M; Furgal, Chris M; Hammill, Mike O; Burness, Gary

2016-01-01

Walruses, Odobenus rosmarus, play a key role in the Arctic ecosystem, including northern Indigenous communities, which are reliant upon walruses for aspects of their diet and culture. However, walruses face varied environmental threats including rising sea-water temperatures and decreasing ice cover. An underappreciated threat may be the large amount of solar ultraviolet radiation (UV) that continues to reach the Arctic as a result of ozone loss. UV has been shown to negatively affect whales. Like whales, walrus skin is unprotected by fur, but in contrast, walruses spend long periods of time hauled-out on land. In this study, we combined the results of histological analyses of skin sections from five Atlantic walruses, Odobenus rosmarus rosmarus, collected in Nunavik (Northern Quebec, Canada) with qualitative data obtained through the interviews of 33 local walrus hunters and Inuit Elders. Histological analyses allowed us to explore UV-induced cellular lesions and interviews with experienced walrus hunters and Elders helped us to study the incidences and temporal changes of UV-induced gross lesions in walruses. At the microscopic scale, we detected a range of skin abnormalities consistent with UV damage. However, currently such UV effects do not seem to be widely observed at the whole-animal level (i.e., absence of skin blistering, erythema, eye cataract) by individuals interviewed. Although walruses may experience skin damage under normal everyday UV exposure, the long-term data from local walrus hunters and Inuit Elders did not report a relation between the increased sun radiation secondary to ozone loss and walrus health.

UV-B-Induced Erythema in Human Skin: The Circadian Clock Is Ticking.

PubMed

Sarkar, Soumyadeep; Gaddameedhi, Shobhan

2018-02-01

Acute exposure of skin to UV-B causes DNA damage and sunburn erythema in both mice and humans. Previous studies documented time-of-day-related differences in sunburn responses after UV-B exposure in mice. Because humans are diurnal and mice are nocturnal, the circadian rhythm in human skin was hypothesized to be in opposite phase to the rhythm in mice. A study by Nikkola et al. demonstrates that humans are more prone to sunburn erythema after evening exposure to solar UV-B radiation as compared with morning exposure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The circadian clock in skin: implications for adult stem cells, tissue regeneration, cancer, aging, and immunity

PubMed Central

Plikus, Maksim V.; Van Spyk, Elyse Noelani; Pham, Kim; Geyfman, Mikhail; Kumar, Vivek; Takahashi, Joseph S.; Andersen, Bogi

2015-01-01

Historically work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as liver, fat and muscle. In recent years, skin is emerging as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging and carcinogenesis. Morphologically skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable and exhibit prominent daily cell proliferation cycles. Hair follicle stem cells also participate in recurrent, long-lasting cycles of regeneration -- the hair growth cycles. Among other advantages of skin is a broad repertoire of available genetic tools enabling the creation of cell-type specific circadian mutants. Also, due to the accessibility of the skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar UV radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it represents a promising model system to further explore the role of the clock in the regulation of the body's immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. The skin also provides opportunities to interrogate clock regulation of tissue metabolism in the context of stem cells and regeneration. Furthermore, many animal species feature prominent seasonal hair molt cycles, offering an attractive model for investigating the role of clock in seasonal organismal behaviors. PMID:25589491

Protective effect of gelatin and gelatin hydrolysate from salmon skin on UV irradiation-induced photoaging of mice skin

NASA Astrophysics Data System (ADS)

Chen, Tiejun; Hou, Hu; Lu, Jiaohan; Zhang, Kai; Li, Bafang

2016-08-01

The objective of this study was to investigate the effect of gelatin (SG) isolated from salmon skin and its hydrolysate (SGH) on photoaging skin, and the mechanism responsible for anti-photoaging. The average molecular weights of SG and SGH were 65 kDa and 873 Da, respectively. The amino acid compositions of SG and SGH were similar. Both of them were abundant in hydrophobic amino acids. Twenty-five peptides were identified from SGH. SG and SGH could improve UV irradiation-induced pathological changes of macroscopical tissue texture and skin morphology. Hydroxyproline content is an indicator of matrix collagen content, SG and SGH could inhibit the decrease of hydroxyproline content in photoaging skin in a dose dependent manner. In addition, SG and SGH could alleviate UV irradiation-induced oxidative damages to skin by increasing the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), increasing the content of glutathione (GSH) and decreasing the content of malonaldehyde (MDA). Moreover, SG and SGH could enhance immune regulation system by increasing the thymus index. Thus, the anti-photoaging mechanisms of SG and SGH were by inhibiting the depletion of antioxidant defense components, involving in the synthesis of collagen and enhancing the function of immune system. Besides, SGH showed a better result in protecting skin from photoaging than SG.

The effects of quercetin-loaded PLGA-TPGS nanoparticles on ultraviolet B-induced skin damages in vivo.

PubMed

Zhu, Xianbing; Zeng, Xiaowei; Zhang, Xudong; Cao, Wei; Wang, Yilin; Chen, Houjie; Wang, Teng; Tsai, Hsiang-I; Zhang, Ran; Chang, Danfeng; He, Shuai; Mei, Lin; Shi, Xiaojun

2016-04-01

Ultraviolet (UV) radiation has deleterious effects on living organisms, and functions as a tumor initiator and promoter. Multiple natural compounds, like quercetin, have been shown the protective effects on UV-induced damage. However, quercetin is extremely hydrophobic and limited by its poor percutaneous permeation and skin deposition. Here, we show that quercetin-loaded PLGA-TPGS nanoparticles could overcome low hydrophilicity of quercetin and improve its anti-UVB effect. Quercetin-loaded NPs can significantly block UVB irradiation induced COX-2 up-expression and NF-kB activation in Hacat cell line. Moreover, PLGA-TPGS NPs could efficiently get through epidermis and reach dermis. Treatment of mice with quercetin-loaded NPs also attenuates UVB irradiation-associated macroscopic and histopathological changes in mice skin. These results demonstrated that copolymer PLGA-TPGS could be used as drug nanocarriers against skin damage and disease. The findings provide an external use of PLGA-TPGS nanocarriers for application in the treatment of skin diseases. Skin is the largest organ in the body and is subjected to ultraviolet (UV) radiation damage daily from the sun. Excessive exposure has been linked to the development of skin cancer. Hence, topically applied agents can play a major role in skin protection. In this article, the authors developed quercetin-loaded PLGA-TPGS nanoparticles and showed their anti-UVB effect. Copyright © 2015 Elsevier Inc. All rights reserved.

Moisture absorption and retention properties, and activity in alleviating skin photodamage of collagen polypeptide from marine fish skin.

PubMed

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.

Innate sensing of microbial products promotes wound-induced skin cancer.

PubMed

Hoste, Esther; Arwert, Esther N; Lal, Rohit; South, Andrew P; Salas-Alanis, Julio C; Murrell, Dedee F; Donati, Giacomo; Watt, Fiona M

2015-01-09

The association between tissue damage, chronic inflammation and cancer is well known. However, the underlying mechanisms are unclear. Here we characterize a mouse model in which constitutive epidermal extracellular-signal-regulated kinase-MAP-kinase signalling results in epidermal inflammation, and skin wounding induces tumours. We show that tumour incidence correlates with wound size and inflammatory infiltrate. Ablation of tumour necrosis factor receptor (TNFR)-1/-2, Myeloid Differentiation primary response gene 88 or Toll-like receptor (TLR)-5, the bacterial flagellin receptor, but not other innate immune sensors, in radiosensitive leukocytes protects against tumour formation. Antibiotic treatment inhibits, whereas injection of flagellin induces, tumours in a TLR-5-dependent manner. TLR-5 is also involved in chemical-induced skin carcinogenesis in wild-type mice. Leukocytic TLR-5 signalling mediates upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in wound-induced papillomas. HMGB1 is elevated in tumours of patients with Recessive Dystrophic Epidermolysis Bullosa, a disease characterized by chronic skin damage. We conclude that in our experimental model the combination of bacteria, chronic inflammation and wounding cooperate to trigger skin cancer.

Innate sensing of microbial products promotes wound-induced skin cancer

PubMed Central

Hoste, Esther; Arwert, Esther N.; Lal, Rohit; South, Andrew P.; Salas-Alanis, Julio C.; Murrell, Dedee F.; Donati, Giacomo; Watt, Fiona M.

2015-01-01

The association between tissue damage, chronic inflammation and cancer is well known. However, the underlying mechanisms are unclear. Here we characterize a mouse model in which constitutive epidermal extracellular-signal-regulated kinase-MAP-kinase signalling results in epidermal inflammation, and skin wounding induces tumours. We show that tumour incidence correlates with wound size and inflammatory infiltrate. Ablation of tumour necrosis factor receptor (TNFR)-1/-2, Myeloid Differentiation primary response gene 88 or Toll-like receptor (TLR)-5, the bacterial flagellin receptor, but not other innate immune sensors, in radiosensitive leukocytes protects against tumour formation. Antibiotic treatment inhibits, whereas injection of flagellin induces, tumours in a TLR-5-dependent manner. TLR-5 is also involved in chemical-induced skin carcinogenesis in wild-type mice. Leukocytic TLR-5 signalling mediates upregulation of the alarmin HMGB1 (High Mobility Group Box 1) in wound-induced papillomas. HMGB1 is elevated in tumours of patients with Recessive Dystrophic Epidermolysis Bullosa, a disease characterized by chronic skin damage. We conclude that in our experimental model the combination of bacteria, chronic inflammation and wounding cooperate to trigger skin cancer. PMID:25575023

Oral administration of hyaluronan prevents skin dryness and epidermal thickening in ultraviolet irradiated hairless mice.

PubMed

Kawada, Chinatsu; Kimura, Mamoru; Masuda, Yasunobu; Nomura, Yoshihiro

2015-12-01

Hyaluronan is a component of the extracellular matrix that plays a role in water retention in tissues. In this study, we orally administered hyaluronans of varying molecular weights (300k and less than 10k) repeatedly to hairless mice exposed to ultraviolet (UV) irradiation and examined their effects on the skin of these mice. UV irradiation induces a marked increase in the epidermal thickness of the dorsal skin and a marked decrease in the skin moisture content; however, orally administered hyaluronan, particularly that with a molecular weight of less than 10k, markedly reversed the increase and decrease in the epidermal thickness and skin moisture content, respectively. Furthermore, on analyzing the mice skin, orally administered hyaluronan with a molecular weight of less than 10k increased the levels of the HAS2 gene expression in the skin. Based on these findings, it is assumed that orally administered hyaluronans, with molecular weight of 300k and less than 10k, reversed UV irradiation-induced skin disturbance. In particular, it was considered that the increase in the skin moisture content by orally administered hyaluronan, with a molecular weight of less than 10k, was related to the effect on skin cells. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro photostability and photoprotection studies of a novel 'multi-active' UV-absorber.

PubMed

Venditti, E; Spadoni, T; Tiano, L; Astolfi, P; Greci, L; Littarru, G P; Damiani, E

2008-08-01

This paper reports on the synthesis and properties of a new UV-absorber (OC-NO) based on the most popular UV filter worldwide, ethylhexyl methoxycinnamate (OMC) in which the methoxy group has been replaced with a pyrrolidine nitroxide bearing antioxidant activity. This sunscreen active has therefore both UV-absorbing and antioxidant properties which could ideally address both the UV-B and UV-A skin photo-damage. For broad-spectrum coverage, the combinations of OC-NO with two commonly used UV-A absorbers (BMDBM and DHHB) were also studied. The results obtained reveal that OC-NO: (a) is as photostable as OMC after UV-A exposure; (b) acts as free radical scavenger as demonstrated by EPR and chemical studies; (c) reduces UV-A and UV-A+BMDBM induced lipid peroxidation in liposomes and cells, measured as reduced TBARS levels and increased C11-BODIPY red fluorescence, respectively; (d) has comparable antioxidant activity to that of vitamin E and BHT commonly used in skin care formulations; (e) is non-cytotoxic to human skin fibroblasts as assessed with the MTT assay when exposed to increasing doses of UV-A; and (f) OC-NO+DHHB is a promising, photostable broad spectrum UV-filter combination that concomitantly reduces UV-induced free radical damage. These results suggest that nitroxide/antioxidant-based UV-absorbers may pave the way for the utilization of 'multi-active' ingredients in sunscreens thereby reducing the number of ingredients in these formulations.

Elevated VEGF-D Modulates Tumor Inflammation and Reduces the Growth of Carcinogen-Induced Skin Tumors.

PubMed

Honkanen, Hanne-Kaisa; Izzi, Valerio; Petäistö, Tiina; Holopainen, Tanja; Harjunen, Vanessa; Pihlajaniemi, Taina; Alitalo, Kari; Heljasvaara, Ritva

2016-07-01

Vascular endothelial growth factor D (VEGF-D) promotes the lymph node metastasis of cancer by inducing the growth of lymphatic vasculature, but its specific roles in tumorigenesis have not been elucidated. We monitored the effects of VEGF-D in cutaneous squamous cell carcinoma (cSCC) by subjecting transgenic mice overexpressing VEGF-D in the skin (K14-mVEGF-D) and VEGF-D knockout mice to a chemical skin carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate treatments. In K14-mVEGF-D mice, tumor lymphangiogenesis was significantly increased and the frequency of lymph node metastasis was elevated in comparison with controls. Most notably, the papillomas regressed more often in K14-mVEGF-D mice than in littermate controls, resulting in a delay in tumor incidence and a remarkable reduction in the total tumor number. Skin tumor growth and metastasis were not obviously affected in the absence of VEGF-D; however, the knockout mice showed a trend for reduced lymphangiogenesis in skin tumors and in the untreated skin. Interestingly, K14-mVEGF-D mice showed an altered immune response in skin tumors. This consisted of the reduced accumulation of macrophages, mast cells, and CD4(+) T-cells and an increase of cytotoxic CD8(+) T-cells. Cytokine profiling by flow cytometry and quantitative real time PCR revealed that elevated VEGF-D expression results in an attenuated Th2 response and promotes M1/Th1 and Th17 polarization in the early stage of skin carcinogenesis, leading to an anti-tumoral immune environment and the regression of primary tumors. Our data suggest that VEGF-D may be beneficial in early-stage tumors since it suppresses the pro-tumorigenic inflammation, while at later stages VEGF-D-induced tumor lymphatics provide a route for metastasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of the Potential of Brazilian Propolis against UV-Induced Oxidative Stress

PubMed Central

Fonseca, Yris Maria; Marquele-Oliveira, Franciane; Vicentini, Fabiana T. M. C.; Furtado, Niege Araçari J. C.; Sousa, João Paulo B.; Lucisano-Valim, Yara M.; Fonseca, Maria José Vieira

2011-01-01

This study investigated the potential use of topically and orally administered propolis extracts to prevent UV irradiation-induced oxidative stress in skin. The results illustrated that green propolis extract (GPE) contained greater amounts of polyphenols, coumaric acid, drupanin, baccharin and artepillin C than did brown propolis extract (BPE). GPE showed higher antioxidant activity than BPE when the IC50 (concentration that caused 50% inhibition) values were compared. Interesting, the oral treatment of hairless mice demonstrated a recovery of 30.0% for GPE and 22.8% for BPE with respect to UV irradiation-induced GSH depletion. The topical pretreatment of animals with both propolis extract solutions recovered around 14.0% of the depleted GSH. However, the employed treatments did not inhibit the increase of cutaneous proteinase secretion/activity caused by irradiation. These findings indicate that despite differences in composition and antioxidant properties, GPE and BPE both successfully prevent UV-induced GSH depletion in vivo and are both promising antioxidant systems against oxidative stress in skin. Based on these findings, complementary studies should be performed to enhance our understanding of the protective effects of propolis extracts in skin. PMID:20953396

MLK3 is a direct target of biochanin A, which plays a role in solar UV-induced COX-2 expression in human keratinocytes.

PubMed

Lim, Tae-Gyu; Kim, Jong-Eun; Jung, Sung Keun; Li, Yan; Bode, Ann M; Park, Jun-Seong; Yeom, Myeong Hun; Dong, Zigang; Lee, Ki Won

2013-10-01

Solar UV (sUV) is an important environmental carcinogen. Recent studies have shown that sUV is associated with numerous human skin disorders, such as wrinkle formation and inflammation. In this study, we found that the isoflavone, biochanin A, inhibited the expression of sUV-induced COX-2, which is a well-characterized sUV-induced enzyme, in both human HaCaT keratinocytes and JB6 P+ mouse skin epidermal cells. Several studies have demonstrated the beneficial effects of biochanin A. However, its direct molecular target is unknown. We found that biochanin A inhibited sUV-induced phosphorylation of MKK4/JNK/c-Jun and MKK3/6/p38/MSK1. Mixed-lineage kinase 3 (MLK3) is an upstream kinase of MKK4 and MKK3/6. Thus, we evaluated the effect of biochanin A on MLK3. We found that sUV-induced MLK3 phosphorylation was not affected, whereas MLK3 kinase activity was significantly suppressed by biochanin A. Furthermore, direct binding of biochanin A in the MLK3 ATP-binding pocket was detected using pull-down assays. Computer modeling supported our observation that MLK3 is a novel target of biochanin A. These results suggest that biochanin A exerts chemopreventive effects by suppressing sUV-induced COX-2 expression mediated through MLK3 inhibition. Copyright © 2013 Elsevier Inc. All rights reserved.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

PubMed

Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélén; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Saati, Talal Al; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer

PubMed Central

Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélène; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Al Saati, Talal; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers. PMID:24203162

Lipid deregulation in UV irradiated skin cells: Role of 25-hydroxycholesterol in keratinocyte differentiation during photoaging.

PubMed

Olivier, Elodie; Dutot, Mélody; Regazzetti, Anne; Dargère, Delphine; Auzeil, Nicolas; Laprévote, Olivier; Rat, Patrice

2017-05-01

Skin photoaging due to UV irradiation is a degenerative process that appears more and more as a growing concern. Lipids, including oxysterols, are involved in degenerative processes; as skin cells contain various lipids, the aim of our study was to evaluate first, changes in keratinocyte lipid levels induced by UV exposure and second, cellular effects of oxysterols in cell morphology and several hallmarks of keratinocyte differentiation. Our mass spectrometry results demonstrated that UV irradiation induces changes in lipid profile of cultured keratinocytes; in particular, ceramides and oxysterols, specifically 25-hydroxycholesterol (25-OH), were increased. Using holography and confocal microscopy analyses, we highlighted cell thickening and cytoskeletal disruption after incubation of keratinocytes with 25-OH. These alterations were associated with keratinocyte differentiation patterns: autophagy stimulation and intracellular calcium increase as measured by cytofluorometry, and increased involucrin level detected by immunocytochemistry. To conclude, oxysterol deregulation could be considered as a common marker of degenerative disorders. During photoaging, 25-OH seems to play a key role inducing morphological changes and keratinocyte differentiation. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

PubMed

Kim, Yoon-Jung; Kim, Ha-Neui; Shin, Mi-Sook; Choi, Byung-Tae

2015-01-01

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.

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

PubMed Central

Kim, Yoon-Jung; Kim, Ha-Neui; Shin, Mi-Sook; Choi, Byung-Tae

2015-01-01

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. PMID:26185518

Fermentable metabolite of Zymomonas mobilis controls collagen reduction in photoaging skin by improving TGF-beta/Smad signaling suppression.

PubMed

Tanaka, Hiroshi; Yamaba, Hiroyuki; Kosugi, Nobuhiko; Mizutani, Hiroshi; Nakata, Satoru

2008-04-01

Solar ultraviolet (UV) irradiation causes damages on human skin and premature skin aging (photoaging). UV-induced reduction of type I collagen in dermis is widely considered primarily induction of wrinkled appearance of photoaging skin. Type I procollagen synthesis is reduced under UV irradiation by blocking transforming growth factor-beta (TGF-beta)/Smad signaling; more specifically, it is down-regulation of TGF-beta type II receptor (T beta RII). Therefore, preventing UV-induced loss of T beta RII results decreased type I collagen reduction in photoaging skin. Zymomonas mobilis is an alcohol fermentable, gram-negative facultative anaerobic bacterium whose effect on skin tissue is scarcely studied. We investigated the protective effects of fermentable metabolite of Z. mobilis (FM of Z. mobilis) against reduction of type I procollagen synthesis of UV-induced down-regulation of T beta RII in human dermal fibroblasts FM of Z. mobilis was obtained from lyophilization of bacterium culture supernatant. The levels of T beta RII and type I procollagen mRNA in human dermal fibroblasts were measured by quantitative real-time RT-PCR, and T beta RII protein levels were assayed by western blotting. T beta RII, type I procollagen, and type I collagen proteins in human dermal fibroblasts or hairless mouse skin were detected by immunostaining. FM of Z. mobilis inhibited down regulation of T beta RII mRNA, and protein levels in UVB irradiated human dermal fibroblasts consequently recover reduced type I procollagen synthesis. These results indicate UVB irradiation inhibits type I procollagen synthesis by suppression of TGF-beta/Smad signaling pathway, and FM of Z. mobilis has inhibitory effect on UVB-induced reduction of type I procollagen synthesis. While short period UVB irradiation decreased both T beta RII and type I procollagen protein levels in hairless mouse skin, topical application of FM of Z. mobilis prevented this decrease. Wrinkle formation in hairless mouse skin surface was accelerated by continuous 5 month UVB irradiation along with a reduction of type I collagen in the dermis, but this change was prevented by topical application of FM of Z. mobilis. From this experimental data, it is suggested that FM of Z. mobilis is effective for suppression of wrinkle formation in photoaging skin by inhibition of type I procollagen synthesis reduction.

Astragaloside IV controls collagen reduction in photoaging skin by improving transforming growth factor-β/Smad signaling suppression and inhibiting matrix metalloproteinase-1.

PubMed

Chen, Bin; Li, Ran; Yan, Ning; Chen, Gang; Qian, Wen; Jiang, Hui-Li; Ji, Chao; Bi, Zhi-Gang

2015-05-01

Exposure to ultraviolet (UV) light reduces levels of type I collagen in the dermis and results in human skin damage and premature skin aging (photoaging). This leads to a wrinkled appearance through the inhibition of transforming growth factor‑β (TGF‑β)/Smad signaling. UV irradiation increases type I collagen degradation through upregulating matrix metalloproteinase (MMP) expression. Astragaloside IV (AST) is one of the major active components extracted from Astragalus membranaceus. However, its multiple anti‑photoaging effects remain to be elucidated. In the present study, the effects of AST against collagen reduction in UV‑induced skin aging in human skin fibroblasts were investigated. The expression of type I procollagen (COL1), MMP‑1, TGF‑βRⅡ and Smad7 were determined using reverse transcription‑polymerase chain reaction, western blotting and ELISA, respectively. UV irradiation inhibits type I collagen production by suppressing the TGF‑β/Smad signaling pathway and increasing COL1 degradation by inducing MMP‑1 expression. Transforming growth factor‑β type II protein and COL1 mRNA decreased but MMP‑1 and Smad7 levels increased in the photoaging model group, which was reversed by topical application of AST. AST prevents collagen reduction from UV irradiation in photoaging skin by improving TGF‑β/Smad signaling suppression and inhibiting MMP‑1, thus AST may be a potential agent against skin photoaging.

VEGF-C and VEGF-D blockade inhibits inflammatory skin carcinogenesis.

PubMed

Alitalo, Annamari K; Proulx, Steven T; Karaman, Sinem; Aebischer, David; Martino, Stefania; Jost, Manuela; Schneider, Nicole; Bry, Maija; Detmar, Michael

2013-07-15

VEGF-C and VEGF-D were identified as lymphangiogenic growth factors and later shown to promote tumor metastasis, but their effects on carcinogenesis are poorly understood. Here, we have studied the effects of VEGF-C and VEGF-D on tumor development in the murine multistep chemical carcinogenesis model of squamous cell carcinoma by using a soluble VEGF-C/VEGF-D inhibitor. After topical treatment with a tumor initiator and repeated tumor promoter applications, transgenic mice expressing a soluble VEGF-C/VEGF-D receptor (sVEGFR-3) in the skin developed significantly fewer squamous cell tumors with a delayed onset when compared with wild-type mice or mice expressing sVEGFR-3 lacking the ligand-binding site. Epidermal proliferation was reduced in the carcinogen-treated transgenic skin, whereas epidermal keratinocyte proliferation in vitro was not affected by VEGF-C or VEGF-D, indicating indirect effects of sVEGFR-3 expression. Importantly, transgenic mouse skin was less sensitive to tumor promoter-induced inflammation, with reduced angiogenesis and blood vessel leakage. Cutaneous leukocytes, especially macrophages, were reduced in transgenic skin without major changes in macrophage polarization or blood monocyte numbers. Several macrophage-associated cytokines were also reduced in transgenic papillomas, although the dermal macrophages themselves did not express VEGFR-3. These findings indicate that VEGF-C/VEGF-D are involved in shaping the inflammatory tumor microenvironment that regulates early tumor progression. Our results support the use of VEGF-C/VEGF-D-blocking agents not only to inhibit metastatic progression, but also during the early stages of tumor growth. ©2013 AACR.

The daidzein metabolite, 6,7,4'-Trihydroxyisoflavone, is a novel inhibitor of PKCα in suppressing solar UV-induced matrix metalloproteinase 1.

PubMed

Lim, Tae-Gyu; Kim, Jong-Eun; Lee, Sung-Young; Park, Jun Seong; Yeom, Myung Hun; Chen, Hanyong; Bode, Ann M; Dong, Zigang; Lee, Ki Won

2014-11-19

Soy isoflavone is an attractive source of functional cosmetic materials with anti-wrinkle, whitening and skin hydration effects. After consumption, the majority of soy isoflavones are converted to their metabolites in the human gastrointestinal tract. To understand the physiological impact of soy isoflavone on the human body, it is necessary to evaluate and address the biological function of its metabolites. In this study, we investigated the effect of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), a major metabolite of daidzein, against solar UV (sUV)-induced matrix metalloproteinases (MMPs) in normal human dermal fibroblasts. MMPs play a critical role in the degradation of collagen in skin, thereby accelerating the aging process of skin. The mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MKK)3/6/p38 and MKK4/c-Jun N-terminal kinases (JNK) signaling pathways are known to modulate MMP-1 function, and their activation by sUV was significantly reduced by 6,7,4'-THIF pretreatment. Our results also indicated that the enzyme activity of protein kinase C (PKC)α, an upstream regulator of MKKs signaling, is suppressed by 6,7,4'-THIF using the in vitro kinase assay. Furthermore, the direct interaction between 6,7,4'-THIF and endogenous PKCα was confirmed using the pull-down assay. Not only sUV-induced MMP-1 expression, but also sUV-induced signaling pathway activation were decreased in PKCα knockdown cells. Overall, we elucidated the inhibitory effect of 6,7,4'-THIF on sUV-induced MMPs and suggest PKCα as its direct molecular target.

Antagonizing Effects and Mechanisms of Afzelin against UVB-Induced Cell Damage

PubMed Central

Shin, Seoung Woo; Jung, Eunsun; Kim, Seungbeom; Kim, Jang-Hyun; Kim, Eui-Gyun; Lee, Jongsung; Park, Deokhoon

2013-01-01

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes, resulting in skin inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effects of UV irradiation is essential. Therefore, in this study, we investigated the protective effects of afzelin, one of the flavonoids, against UV irradiation in human keratinocytes and epidermal equivalent models. Spectrophotometric measurements revealed that the afzelin extinction maxima were in the UVB and UVA range, and UV transmission below 376 nm was <10%, indicating UV-absorbing activity of afzelin. In the phototoxicity assay using the 3T3 NRU phototoxicity test (3T3-NRU-PT), afzelin presented a tendency to no phototoxic potential. In addition, in order to investigate cellular functions of afzelin itself, cells were treated with afzelin after UVB irradiation. In human keratinocyte, afzelin effectively inhibited the UVB-mediated increase in lipid peroxidation and the formation of cyclobutane pyrimidine dimers. Afzelin also inhibited UVB-induced cell death in human keratinocytes by inhibiting intrinsic apoptotic signaling. Furthermore, afzelin showed inhibitory effects on UVB-induced release of pro-inflammatory mediators such as interleukin-6, tumor necrosis factor-α, and prostaglandin-E2 in human keratinocytes by interfering with the p38 kinase pathway. Using an epidermal equivalent model exposed to UVB radiation, anti-apoptotic activity of afzelin was also confirmed together with a photoprotective effect at the morphological level. Taken together, our results suggest that afzelin has several cellular activities such as DNA-protective, antioxidant, and anti-inflammatory as well as UV-absorbing activity and may protect human skin from UVB-induced damage by a combination of UV-absorbing and cellular activities. PMID:23626759

Clusterin associates with altered elastic fibers in human photoaged skin and prevents elastin from ultraviolet-induced aggregation in vitro.

PubMed

Janig, Elke; Haslbeck, Martin; Aigelsreiter, Ariane; Braun, Nathalie; Unterthor, Daniela; Wolf, Peter; Khaskhely, Noor M; Buchner, Johannes; Denk, Helmut; Zatloukal, Kurt

2007-11-01

Clusterin is a secreted glycoprotein with stress-induced expression in various diseased and aged tissues. It shares basic features with small heat shock proteins because it may stabilize proteins in a folding-competent state. Besides its presence in all human body fluids, clusterin associates with altered extracellular matrix proteins, such as beta-amyloid in Alzheimer senile plaques in the brain. Because dermal connective tissue alterations occur because of aging and UV radiation, we explored the occurrence of clusterin in young, aged, and sun-exposed human skin. Immunohistochemical analysis showed that clusterin is constantly associated with altered elastic fibers in aged human skin. Elastotic material of sun-damaged skin (solar elastosis), in particular, revealed a strong staining for clusterin. Because of the striking co-localization of clusterin with abnormal elastic material, we investigated the interaction of clusterin with elastin in vitro. A chaperone assay was established in which elastin was denatured by UV irradiation in the absence or presence of clusterin. This assay demonstrated that clusterin exerted a chaperone-like activity and effectively inhibited UV-induced aggregation of elastin. The interaction of both proteins was further analyzed by electron microscopy, size exclusion chromatography, and mass spectrometry, in which clusterin was found in a stable complex with elastin after UV exposure.

Clusterin Associates with Altered Elastic Fibers in Human Photoaged Skin and Prevents Elastin from Ultraviolet-Induced Aggregation in Vitro

PubMed Central

Janig, Elke; Haslbeck, Martin; Aigelsreiter, Ariane; Braun, Nathalie; Unterthor, Daniela; Wolf, Peter; Khaskhely, Noor M.; Buchner, Johannes; Denk, Helmut; Zatloukal, Kurt

2007-01-01

Clusterin is a secreted glycoprotein with stress-induced expression in various diseased and aged tissues. It shares basic features with small heat shock proteins because it may stabilize proteins in a folding-competent state. Besides its presence in all human body fluids, clusterin associates with altered extracellular matrix proteins, such as β-amyloid in Alzheimer senile plaques in the brain. Because dermal connective tissue alterations occur because of aging and UV radiation, we explored the occurrence of clusterin in young, aged, and sun-exposed human skin. Immunohistochemical analysis showed that clusterin is constantly associated with altered elastic fibers in aged human skin. Elastotic material of sun-damaged skin (solar elastosis), in particular, revealed a strong staining for clusterin. Because of the striking co-localization of clusterin with abnormal elastic material, we investigated the interaction of clusterin with elastin in vitro. A chaperone assay was established in which elastin was denatured by UV irradiation in the absence or presence of clusterin. This assay demonstrated that clusterin exerted a chaperone-like activity and effectively inhibited UV-induced aggregation of elastin. The interaction of both proteins was further analyzed by electron microscopy, size exclusion chromatography, and mass spectrometry, in which clusterin was found in a stable complex with elastin after UV exposure. PMID:17872975

Towards a Better Understanding of the Effects of UV on Atlantic Walruses, Odobenus rosmarus rosmarus: A Study Combining Histological Data with Local Ecological Knowledge

PubMed Central

Martinez-Levasseur, Laura M.; Furgal, Chris M.; Hammill, Mike O.; Burness, Gary

2016-01-01

Walruses, Odobenus rosmarus, play a key role in the Arctic ecosystem, including northern Indigenous communities, which are reliant upon walruses for aspects of their diet and culture. However, walruses face varied environmental threats including rising sea-water temperatures and decreasing ice cover. An underappreciated threat may be the large amount of solar ultraviolet radiation (UV) that continues to reach the Arctic as a result of ozone loss. UV has been shown to negatively affect whales. Like whales, walrus skin is unprotected by fur, but in contrast, walruses spend long periods of time hauled-out on land. In this study, we combined the results of histological analyses of skin sections from five Atlantic walruses, Odobenus rosmarus rosmarus, collected in Nunavik (Northern Quebec, Canada) with qualitative data obtained through the interviews of 33 local walrus hunters and Inuit Elders. Histological analyses allowed us to explore UV-induced cellular lesions and interviews with experienced walrus hunters and Elders helped us to study the incidences and temporal changes of UV-induced gross lesions in walruses. At the microscopic scale, we detected a range of skin abnormalities consistent with UV damage. However, currently such UV effects do not seem to be widely observed at the whole-animal level (i.e., absence of skin blistering, erythema, eye cataract) by individuals interviewed. Although walruses may experience skin damage under normal everyday UV exposure, the long-term data from local walrus hunters and Inuit Elders did not report a relation between the increased sun radiation secondary to ozone loss and walrus health. PMID:27049757

Enhanced Repair of UV-Induced DNA Damage by 1,25-Dihydroxyvitamin D3 in Skin Is Linked to Pathways that Control Cellular Energy.

PubMed

Rybchyn, Mark Stephen; De Silva, Warusavithana Gunawardena Manori; Sequeira, Vanessa Bernadette; McCarthy, Bianca Yuko; Dilley, Anthony Vincent; Dixon, Katie Marie; Halliday, Gary Mark; Mason, Rebecca Sara

2018-05-01

Inadequately repaired post-UV DNA damage results in skin cancers. DNA repair requires energy but skin cells have limited capacity to produce energy after UV insult. We examined whether energy supply is important for DNA repair after UV exposure, in the presence of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), which reduces UV-induced DNA damage and photocarcinogenesis in a variety of models. After UV exposure of primary human keratinocytes, the addition of 1,25(OH) 2 D 3 increased unscheduled DNA synthesis, a measure of DNA repair. Oxidative phosphorylation was depleted in UV-irradiated keratinocytes to undetectable levels within an hour of UV irradiation. Treatment with 1,25(OH) 2 D 3 but not vehicle increased glycolysis after UV. 2-Deoxyglucose-dependent inhibition of glycolysis abolished the reduction in cyclobutane pyrimidine dimers by 1,25(OH) 2 D 3 , whereas inhibition of oxidative phosphorylation had no effect. 1,25(OH) 2 D 3 increased autophagy and modulated PINK1/Parkin consistent with enhanced mitophagy. These data confirm that energy availability is limited in keratinocytes after exposure to UV. In the presence of 1,25(OH) 2 D 3 , glycolysis is enhanced along with energy-conserving processes such as autophagy and mitophagy, resulting in increased repair of cyclobutane pyrimidine dimers and decreased oxidative DNA damage. Increased energy availability in the presence of 1,25(OH) 2 D 3 is an important contributor to DNA repair in skin after UV exposure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Flt3 is a target of coumestrol in protecting against UVB-induced skin photoaging.

PubMed

Park, Gaeun; Baek, Sohee; Kim, Jong-Eun; Lim, Tae-gyu; Lee, Charles C; Yang, Hee; Kang, Young-Gyu; Park, Jun Seong; Augustin, Martin; Mrosek, Michael; Lee, Chang Yong; Dong, Zigang; Huber, Robert; Lee, Ki Won

2015-12-01

While skin aging is a naturally occurring process by senescence, exposure to ultraviolet (UV) radiation accelerates wrinkle formation and sagging of skin. UV induces skin aging by degrading collagen via activating matrix metalloproteinases (MMPs). In this study, we show that coumestrol, a metabolite of the soybean isoflavone daidzein, has a preventive effect on skin photoaging in three-dimensional human skin equivalent model. Coumestrol inhibited UVB-induced MMP-1 expression and activity. Whole human kinase profiling assay identified FLT3 kinase as a novel target protein of coumestrol in UVB-induced signaling pathway in skin. Coumestrol suppresses FLT3 kinase activity, and subsequently, Ras/MEK/ERK and Akt/p70 ribosomal S6 kinase pathway. This suppresses AP-1 activity and in turn, diminishes MMP-1 gene transcription. Using X-ray crystallography, the binding of coumestrol to FLT3 was defined and implied ATP-competitive inhibition. Residues Lys644 and Phe830 showed local changes to accommodate coumestrol in the ATP-binding pocket. 4-APIA, a pharmacological inhibitor of FLT3, inhibited MMP-1 expression and induced signal transduction changes similar to coumestrol. Taken together, coumestrol inhibits UVB-induced MMP-1 expression by suppressing FLT3 kinase activity. These findings suggest that coumestrol is a novel dietary compound with potential application in preventing and improving UVB-associated skin aging. Copyright © 2015 Elsevier Inc. All rights reserved.

Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arumugam, Aadithya; Weng, Zhiping; Chaudhary, Sandeep C.

Highlights: • Targeting ODC to hair follicle augments skin carcinogenesis and invasive SCCs. • Hair follicle ODC expands stem cell compartment carrying CD34{sup +}/K15{sup +}/p63{sup +} keratinocytes. • Negatively regulated Notch1 is associated with expansion of stem cell compartment. - Abstract: Over-expression of ornithine decarboxylase (ODC) is known to be involved in the epidermal carcinogenesis. However, the mechanism by which it enhances skin carcinogenesis remains undefined. Recently, role of stem cells localized in various epidermal compartments has been shown in the pathogenesis of skin cancer. To direct ODC expression in distinct epidermal compartments, we have developed keratin 6 (K6)-ODC/SKH-1 andmore » keratin 14 (K14)-ODC/SKH-1 mice and employed them to investigate the role of ODC directed to these epidermal compartments on UVB-induced carcinogenesis. K6-driven ODC over-expression directed to outer root sheath (ORS) of hair follicle was more effective in augmenting tumorigenesis as compared to mice where K14-driven ODC expression was directed to inter-follicular epidermal keratinocytes. Chronically UVB-irradiated K6-ODC/SKH-1 developed 15 ± 2.5 tumors/mouse whereas K14-ODC/SKH-1 developed only 6.8 ± 1.5 tumors/mouse. K6-ODC/SKH-1 showed augmented UVB-induced proliferation and much higher pro-inflammatory responses than K14-ODC/SKH-1 mice. Tumors induced in K6-ODC/SKH-1 were rapidly growing, invasive and ulcerative squamous cell carcinoma (SCC) showing decreased expression of epidermal polarity marker E-cadherin and enhanced mesenchymal marker, fibronectin. Interestingly, the number of CD34/CK15/p63 positive stem-like cells was significantly higher in chronically UVB-irradiated K6-ODC/SKH-1 as compared to K14-ODC/SKH-1 mice. Reduced Notch1 expression was correlated with the expansion of stem cell compartment in these animals. However, other signaling pathways such as DNA damage response or mTOR signaling pathways were not significantly different in tumors induced in these two murine models suggesting the specificity of Notch pathway in this regard. These data provide a novel role of ODC in augmenting tumorigenesis via negatively regulated Notch-mediated expansion of stem cell compartment.« less

UV-Induced Triggering of a Biomechanical Initiation Switch Within Collagen Promotes Development of a Melanoma-Permissive Microenvironment in the Skin

DTIC Science & Technology

2012-09-01

addition, our new data suggest that pre-treating mice with anti-HU177 antibody inhibited UVB -induced accumulation of mast cells in the skin. Moreover, pre...work is provided below. Our previous studies have indicated that UVA and UVB irradiation can dose dependently trigger conformational changes in both...vitro following UV-irradiation was unlikely do to thermal denaturation. Interestingly, macrophage adhesion to UVB irradiated collagen type-IV but not

Protective effects of skin permeable epidermal and fibroblast growth factor against ultraviolet-induced skin damage and human skin wrinkles.

PubMed

An, Jae Jin; Eum, Won Sik; Kwon, Hyuck Se; Koh, Jae Sook; Lee, Soo Yun; Baek, Ji Hwoon; Cho, Yong-Jun; Kim, Dae Won; Han, Kyu Huyng; Park, Jinseu; Jang, Sang Ho; Choi, Soo Young

2013-12-01

Epidermal and fibroblast growth factor (EGF and FGF1) proteins play an important role in the regeneration and proliferation of skin cells. EGF and FGF1 have considerable potential as possible therapeutic or cosmetic agents for the treatment of skin damage including wrinkles. Using protein transduction domains (PTD), we investigated whether PTD-EGF and FGF1 transduced into skin cells and tissue. Transduced proteins showed protective effects in a UV-induced skin damage model as well as against skin wrinkles. Transduced PTD-EGF and FGF1 proteins were detected by immunofluorescence and immunohistochemistry. The effects of PTD-EGF and FGF1 were examined by WST assay, Western blotting, immunohistochemistry, and skin wrinkle parameters. The PTD-EGF and FGF1 increased cell proliferation and collagen type 1 alpha 1 protein accumulation in skin tissue. Also, PTD-EGF and FGF1 inhibited UV-induced skin damage. Furthermore, topical application of PTD-EGF and FGF1 contained ampoules which were considered to improve the wrinkle parameters of human skin. These results show that PTD-EGF and FGF1 can be a potential therapeutic or cosmetic agent for skin damaged and injury including wrinkles and aging. © 2013 Wiley Periodicals, Inc.

Ultraviolet laser effects on the cornea

NASA Astrophysics Data System (ADS)

Zuclich, Joseph A.

1990-07-01

Ultraviolet radiation in the ambient environment or from artificial sources may pose both acute and chronic hazards to the skin and the ocular tissues. In general terrestrial conditions have evolved such that there are only narrow safety margins between ambient UV levels and exposure levels harmful to the human. Obvious examples of acute consequences ofUV overexposure are sunburn and snowblindness as well as analogous conditions induced by artificial sources such as the welder''s arc mercury vapor lamps and UV-emitting lasers. Further chronic UV exposure is strongly implicated as a causative agent in certain types of cataract and skin cancer. This presentation will summarize a number of specific cases where UV radiation affected the primate cornea. Data presented will include the action spectra for far- and near-UV induced ocular damage the pulsewidth and total energy dependencies of ocular thresholds studies of cumulative effects of repeated UV exposures and quantitative determinations of tissue repair or recovery rates. Depending on the exposure parameters utilized photochemical thermal or photoablative damage mechanisms may prevail. 1.

Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.

PubMed

Rao, Velidi H; Vogel, Kristen; Yanagida, Jodi K; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K; Hansen, Laura A

2015-10-01

Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness. © 2014 Wiley Periodicals, Inc.

Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis.

PubMed

Lim, Chae Jin; Lee, Yong-Moon; Kang, Seung Goo; Lim, Hyung W; Shin, Kyong-Oh; Jeong, Se Kyoo; Huh, Yang Hoon; Choi, Suin; Kor, Myungho; Seo, Ho Seong; Park, Byeong Deog; Park, Keedon; Ahn, Jeong Keun; Uchida, Yoshikazu; Park, Kyungho

2017-09-01

Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by SA-β-gal staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.

Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection.

PubMed

Spry, Malinda L; Vanover, Jillian C; Scott, Timothy; Abona-Ama, Osama; Wakamatsu, Kazumasa; Ito, Shosuke; D'Orazio, John A

2009-04-01

We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.

The Response of Human Skin Commensal Bacteria as a Reflection of UV Radiation: UV-B Decreases Porphyrin Production

PubMed Central

Wang, Yanhan; Zhu, Wenhong; Shu, Muya; Jiang, Yong; Gallo, Richard L.; Liu, Yu-Tsueng; Huang, Chun-Ming

2012-01-01

Recent global radiation fears reflect the urgent need for a new modality that can simply determine if people are in a radiation risk of developing cancer and other illnesses. Ultraviolet (UV) radiation has been thought to be the major risk factor for most skin cancers. Although various biomarkers derived from the responses of human cells have been revealed, detection of these biomarkers is cumbersome, probably requires taking live human tissues, and varies significantly depending on human immune status. Here we hypothesize that the reaction of Propionibacterium acnes (P. acnes), a human resident skin commensal, to UV radiation can serve as early surrogate markers for radiation risk because the bacteria are immediately responsive to radiation. In addition, the bacteria can be readily accessible and exposed to the same field of radiation as human body. To test our hypothesis, P. acnes was exposed to UV-B radiation. The production of porphyrins in P. acnes was significantly reduced with increasing doses of UV-B. The porphyrin reduction can be detected in both P. acnes and human skin bacterial isolates. Exposure of UV-B to P. acnes- inoculated mice led to a significant decrease in porphyrin production in a single colony of P. acnes and simultaneously induced the formation of cyclobutane pyrimidine dimers (CPD) in the epidermal layers of mouse skin. Mass spectrometric analysis via a linear trap quadrupole (LTQ)-Orbitrap XL showed that five peptides including an internal peptide (THLPTGIVVSCQNER) of a peptide chain release factor 2 (RF2) were oxidized by UV-B. Seven peptides including three internal peptides of 60 kDa chaperonin 1 were de-oxidized by UV-B. When compared to UV-B, gamma radiation also decreased the porphyrin production of P. acnes in a dose-dependent manner, but induced a different signature of protein oxidation/de-oxidation. We highlight that uncovering response of skin microbiome to radiation will facilitate the development of pre-symptomatic diagnosis of radiation risk in a battlefield exposure, nuclear accidents, terrorist attacks, or cancer imaging/therapy. PMID:23133525

The response of human skin commensal bacteria as a reflection of UV radiation: UV-B decreases porphyrin production.

PubMed

Wang, Yanhan; Zhu, Wenhong; Shu, Muya; Jiang, Yong; Gallo, Richard L; Liu, Yu-Tsueng; Huang, Chun-Ming

2012-01-01

Recent global radiation fears reflect the urgent need for a new modality that can simply determine if people are in a radiation risk of developing cancer and other illnesses. Ultraviolet (UV) radiation has been thought to be the major risk factor for most skin cancers. Although various biomarkers derived from the responses of human cells have been revealed, detection of these biomarkers is cumbersome, probably requires taking live human tissues, and varies significantly depending on human immune status. Here we hypothesize that the reaction of Propionibacterium acnes (P. acnes), a human resident skin commensal, to UV radiation can serve as early surrogate markers for radiation risk because the bacteria are immediately responsive to radiation. In addition, the bacteria can be readily accessible and exposed to the same field of radiation as human body. To test our hypothesis, P. acnes was exposed to UV-B radiation. The production of porphyrins in P. acnes was significantly reduced with increasing doses of UV-B. The porphyrin reduction can be detected in both P. acnes and human skin bacterial isolates. Exposure of UV-B to P. acnes- inoculated mice led to a significant decrease in porphyrin production in a single colony of P. acnes and simultaneously induced the formation of cyclobutane pyrimidine dimers (CPD) in the epidermal layers of mouse skin. Mass spectrometric analysis via a linear trap quadrupole (LTQ)-Orbitrap XL showed that five peptides including an internal peptide (THLPTGIVVSCQNER) of a peptide chain release factor 2 (RF2) were oxidized by UV-B. Seven peptides including three internal peptides of 60 kDa chaperonin 1 were de-oxidized by UV-B. When compared to UV-B, gamma radiation also decreased the porphyrin production of P. acnes in a dose-dependent manner, but induced a different signature of protein oxidation/de-oxidation. We highlight that uncovering response of skin microbiome to radiation will facilitate the development of pre-symptomatic diagnosis of radiation risk in a battlefield exposure, nuclear accidents, terrorist attacks, or cancer imaging/therapy.

Effects of collagen and collagen hydrolysate from jellyfish umbrella on histological and immunity changes of mice photoaging.

PubMed

Fan, Jian; Zhuang, Yongliang; Li, Bafang

2013-01-17

Jellyfish collagen (JC) was extracted from jellyfish umbrella and hydrolyzed to prepare jellyfish collagen hydrolysate (JCH). The effects of JC and JCH on UV-induced skin damage of mice were evaluated by the skin moisture, microscopic analyses of skin and immunity indexes. The skin moisture analyses showed that moisture retention ability of UV-induced mice skin was increased by JC and JCH. Further histological analysis showed that JC and JCH could repair the endogenous collagen and elastin protein fibers, and could maintain the natural ratio of type I to type III collagen. The immunity indexes showed that JC and JCH play a role in enhancing immunity of photoaging mice in vivo. JCH showed much higher protective ability than JC. These results suggest that JCH as a potential novel antiphotoaging agent from natural resources.

Photoprotection against UV-induced damage by skin-derived precursors in hairless mice.

PubMed

Xian, Dehai; Gao, Xiaoqing; Xiong, Xia; Xu, Jixiang; Yang, Lingyu; Pan, Lun; Zhong, Jianqiao

2017-10-01

Skin photodamage is associated with UV-induced overproduction of reactive oxygen species (ROS) and the inactivation of NF-E2-related factor 2 (Nrf2). Skin-derived precursor cells (SKPs), a population of dermal stem cells, are considered to be involved in wound repair and skin regeneration through the activation of Nrf2. However, no reports concentrate on the treatment of skin photodamage with SKPs. To investigate the photoprotective role of SKPs against UV-induced damage in mice. Fifty Balb/c hairless mice were divided into five groups (n=10), namely, normal (no intervention), model, prevention, treatment, and control groups. The latter four groups were dorsally exposed to UVA+UVB irradiation over a 2-week period. Mice in the prevention group received weekly SKP injections for 2weeks the day before irradiation. Mice in the treatment and Hanks groups received a two-time injection of SKPs and Hanks, respectively, after irradiation. One week after final intervention, skin appearance, pathological alterations, and oxidative indicators were evaluated by enzyme-linked immunosorbent assay, immunohistochemical analysis, and western blotting. After irradiation, lesions were observed on the dorsal skin of mice, including erythema, edema, scales, and wrinkles; however, these were significantly ameliorated by subcutaneous SKP injection. Hyperkeratosis, acanthosis, and spongiosis in the epidermis, as well as dermal papillae edema and inflammatory cell infiltration, were observed in both model and control groups; however, these conditions resolved with either pretreatment or posttreatment with SKPs. In addition, SKPs increased Nrf2, heme oxygenase-1, glutathione peroxidase, superoxide dismutase, catalase, and gluthathione expression, while decreasing levels of ROS, MDA, and H 2 O 2 . These findings suggest that SKPs have a photoprotective role against UV-induced damage in mice, which may be associated with their ability to scavenge photo-oxidative insults and activate Nrf2. Copyright © 2017 Elsevier B.V. All rights reserved.

Germicidal Efficacy and Mammalian Skin Safety of 222-nm UV Light

PubMed Central

Buonanno, Manuela; Ponnaiya, Brian; Welch, David; Stanislauskas, Milda; Randers-Pehrson, Gerhard; Smilenov, Lubomir; Lowy, Franklin D.; Owens, David M.; Brenner, David J.

2017-01-01

We have previously shown that 207-nm ultraviolet (UV) light has similar antimicrobial properties as typical germicidal UV light (254 nm), but without inducing mammalian skin damage. The biophysical rationale is based on the limited penetration distance of 207-nm light in biological samples (e.g. stratum corneum) compared with that of 254-nm light. Here we extended our previous studies to 222-nm light and tested the hypothesis that there exists a narrow wavelength window in the far-UVC region, from around 200–222 nm, which is significantly harmful to bacteria, but without damaging cells in tissues. We used a krypton-chlorine (Kr-Cl) excimer lamp that produces 222-nm UV light with a bandpass filter to remove the lower- and higher-wavelength components. Relative to respective controls, we measured: 1. in vitro killing of methicillin-resistant Staphylococcus aureus (MRSA) as a function of UV fluence; 2. yields of the main UV-associated premutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in a 3D human skin tissue model in vitro; 3. eight cellular and molecular skin damage endpoints in exposed hairless mice in vivo. Comparisons were made with results from a conventional 254-nm UV germicidal lamp used as positive control. We found that 222-nm light kills MRSA efficiently but, unlike conventional germicidal UV lamps (254 nm), it produces almost no premutagenic UV-associated DNA lesions in a 3D human skin model and it is not cytotoxic to exposed mammalian skin. As predicted by biophysical considerations and in agreement with our previous findings, far-UVC light in the range of 200–222 nm kills bacteria efficiently regardless of their drug-resistant proficiency, but without the skin damaging effects associated with conventional germicidal UV exposure. PMID:28225654

Germicidal Efficacy and Mammalian Skin Safety of 222-nm UV Light.

PubMed

Buonanno, Manuela; Ponnaiya, Brian; Welch, David; Stanislauskas, Milda; Randers-Pehrson, Gerhard; Smilenov, Lubomir; Lowy, Franklin D; Owens, David M; Brenner, David J

2017-04-01

We have previously shown that 207-nm ultraviolet (UV) light has similar antimicrobial properties as typical germicidal UV light (254 nm), but without inducing mammalian skin damage. The biophysical rationale is based on the limited penetration distance of 207-nm light in biological samples (e.g. stratum corneum) compared with that of 254-nm light. Here we extended our previous studies to 222-nm light and tested the hypothesis that there exists a narrow wavelength window in the far-UVC region, from around 200-222 nm, which is significantly harmful to bacteria, but without damaging cells in tissues. We used a krypton-chlorine (Kr-Cl) excimer lamp that produces 222-nm UV light with a bandpass filter to remove the lower- and higher-wavelength components. Relative to respective controls, we measured: 1. in vitro killing of methicillin-resistant Staphylococcus aureus (MRSA) as a function of UV fluence; 2. yields of the main UV-associated premutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) in a 3D human skin tissue model in vitro; 3. eight cellular and molecular skin damage endpoints in exposed hairless mice in vivo. Comparisons were made with results from a conventional 254-nm UV germicidal lamp used as positive control. We found that 222-nm light kills MRSA efficiently but, unlike conventional germicidal UV lamps (254 nm), it produces almost no premutagenic UV-associated DNA lesions in a 3D human skin model and it is not cytotoxic to exposed mammalian skin. As predicted by biophysical considerations and in agreement with our previous findings, far-UVC light in the range of 200-222 nm kills bacteria efficiently regardless of their drug-resistant proficiency, but without the skin damaging effects associated with conventional germicidal UV exposure.

Fisetin Ameliorated Photodamage by Suppressing the Mitogen-Activated Protein Kinase/Matrix Metalloproteinase Pathway and Nuclear Factor-κB Pathways.

PubMed

Chiang, Hsiu-Mei; Chan, Shih-Yun; Chu, Yin; Wen, Kuo-Ching

2015-05-13

Ultraviolet (UV) irradiation is one of the most important extrinsic factors contributing to skin photodamage. After UV irradiation, a series of signal transductions in the skin will be activated, leading to inflammatory response and photoaged skin. In this study, fisetin, a flavonol that exists in fruits and vegetables, was investigated for its photoprotective effects. The results revealed that 5-25 μM fisetin inhibits cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP)-1, MMP-3, MMP-9 expression induced by ultraviolet B (UVB) irradiation in human skin fibroblasts. In addition, fisetin suppressed UVB-induced collagen degradation. With regard to its effect on upper-stream signal transduction, we found that fisetin reduced the expression of ultraviolet (UV)-induced ERK, JNK, and p38 phosphorylation in the mitogen-activated protein kinase (MAP kinase) pathway. Furthermore, fisetin reduced inhibitor κB (IκB) degradation and increased the amount of p65, which is a major subunit of nuclear factor-κB (NF-κB), in cytoplasm. It also suppressed NF-κB translocated to the nucleus and inhibited cAMP response element-binding protein (CREB) Ser-133 phosphorylation level in the phosphoinositide 3-kinase/protein kinase B/CREB (PI3K/AKT/CREB) pathway. Finally, fisetin inhibited UV-induced intracellular reactive oxygen species (ROS), prostaglandin E2 (PGE2), and nitric oxide (NO) generation. The mentioned effects and mechanisms suggest that fisetin can be used in the development of photoprotective agents.

Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis.

PubMed

Wattenberg, Elizabeth V

2007-01-01

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na(+),K(+)-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

Palytoxin: Exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis

PubMed Central

Wattenberg, Elizabeth V.

2006-01-01

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multi-stage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multi-stage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol-12-myristate-13-acetate or PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling, and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated. PMID:16855216

Identification of a possible susceptibility locus for UVB-induced skin tanning phenotype in Korean females using genomewide association study.

PubMed

Kwak, Taek-Jong; Chang, Yun-Hee; Shin, Young-Ah; Shin, Jung-Min; Kim, Ji-Hye; Lim, Seul-Ki; Lee, Sang-Hwha; Lee, Min-Geol; Yoon, Tae-Jin; Kim, Chang-Deok; Lee, Jeung-Hoon; Koh, Jae Sook; Seo, Young Kyoung; Chang, Min-Youl; Lee, Young

2015-12-01

A two-stage genomewide association (GWA) analysis was conducted to investigate the genetic factors influencing ultraviolet (UV)-induced skin pigmentation in Korean females after UV exposure. Previously, a GWA study evaluating ~500 000 single nucleotide polymorphisms (SNPs) in 99 Korean females identified eight SNPs that were highly associated with tanning ability. To confirm these associations, we genotyped the SNPs in an independent replication study (112 Korean females). We found that a novel SNP in the intron of the WW domain-containing oxidoreductase (WWOX) gene yielded significant replicated associations with skin tanning ability (P-value = 1.16 × 10(-4) ). To understand the functional consequences of this locus located in the non-coding region, we investigated the role of WWOX in human melanocytes using a recombinant adenovirus expressing a microRNA specific for WWOX. Inhibition of WWOX expression significantly increased the expression and activity of tyrosinase in human melanocytes. Taken together, our results suggest that genetic variants in the intronic region of WWOX could be determinants in the UV-induced tanning ability of Korean females. WWOX represents a new candidate gene to evaluate the molecular basis of the UV-induced tanning ability in individuals. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Grape seed proanthocyanidines and skin cancer prevention: Inhibition of oxidative stress and protection of immune system

PubMed Central

Katiyar, Santosh K.

2008-01-01

Overexposure of the skin to ultraviolet (UV) radiation has a variety of adverse effects on human health, including the development of skin cancers. There is a need to develop nutrition-based efficient chemopreventive strategies. The proanthocyanidins present in grape seeds (Vitis vinifera) have been shown to have some biological effects, including prevention of photocarcinogenesis. The present communication discusses the in vitro and in vivo studies of the possible protective effect of grape seed proanthocyanidins (GSPs) and the molecular mechanism for these effects. In SKH-1 hairless mice, dietary supplementation with GSPs is associated with a decrease of UVB-induced skin tumor development in terms of tumor incidence, tumor multiplicity, and a decrease in the malignant transformation of papillomas to carcinomas. It is suggested that the chemopreventive effects of dietary GSPs are mediated through the attenuation of UV-induced: (a) oxidative stress; (b) activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways; and (c) immunosuppression through alterations in immunoregulatory cytokines. Collectively, these studies indicate protective potential of GSPs against experimental photocarcinogenesis in SKH-1 hairless mice, and the possible mechanisms of action of GSPs, and suggest that dietary GSPs could be useful in the attenuation of the adverse UV-induced health effects in human skin. PMID:18384090

Occupational skin cancer induced by ultraviolet radiation and its prevention.

PubMed

Diepgen, T L; Fartasch, M; Drexler, H; Schmitt, J

2012-08-01

Skin cancer is by far the most common kind of cancer diagnosed in many western countries and ultraviolet radiation is the most important risk factor for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Although employees at several workplaces are exposed to increased levels of UV radiation, skin cancer due to long-term intense occupational exposure to UV radiation is often not considered as occupational disease. The actually available evidence in the epidemiological literature clearly indicates that occupational UV radiation exposure is a substantial and robust risk factor for the development of cutaneous SCC and also clearly shows a significant risk for developing BCC. There is enough scientific evidence that outdoor workers have an increased risk of developing work-related occupational skin cancer due to natural UV radiation exposure and adequate prevention strategies must be implemented. The three measures which are successful and of particular importance in the prevention of nonmelanoma skin cancer in outdoor workers are changes in behaviour regarding awareness of health and disease resulting from exposure to natural UV radiation, protection from direct UV radiation by wearing suitable clothing, and regular and correct use of appropriate sunscreens. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

UVA-UVB photoprotective activity of topical formulations containing Morinda citrifolia extract.

PubMed

Serafini, Mairim Russo; Detoni, Cassia Britto; Menezes, Paula dos Passos; Pereira Filho, Rose Nely; Fortes, Vanessa Silveira; Vieira, Maria José Fonseca; Guterres, Sílvia Stanisçuaski; Cavalcanti de Albuquerque Junior, Ricardo Luiz; Araújo, Adriano Antunes de Souza

2014-01-01

Exposure to solar radiation, particularly its ultraviolet (UV) component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formations, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. The beneficial photoprotective effects of topical formulations with the extract, Morinda citrifolia, have not been investigated. This present study aims to investigate the potential benefits of M. citrifolia topical application on the dorsal skin of mice, exposed to UVA-UVB light. Using 7 days of treatment, [before (baseline values) and 20 h after UV exposure], the thickness, skin barrier damage (TEWL), erythema, and histological alterations were evaluated. The results showed that the formulations containing the extract protected the skin against UV-induced damage.

A novel research model for evaluating sunscreen protection in the UV-A1.

PubMed

Figueiredo, Sônia Aparecida; de Moraes, Dayane Cristina; Vilela, Fernanda Maria Pinto; de Faria, Amanda Natalina; Dos Santos, Marcelo Henrique; Fonseca, Maria José Vieira

2018-01-01

The use of a broad spectrum sunscreen is considered one of the main and most popular measures for preventing the damaging effects of ultraviolet radiation (UVR) on the skin. In this study we have developed a novel in vitro method to assess sunscreens efficacy to protect calcineurin enzyme activity, a skin cell marker. The photoprotective efficacy of sunscreen products was assessed by measuring the UV-A1 radiation-induced depletion of calcineurin (Cn) enzyme activity in primary neonatal human dermal fibroblast (HDFn) cell lysates. After exposure to 24J/cm 2 UV-A1 radiation, the sunscreens containing larger amounts of UV-A1 filters (brand B), the astaxanthin (UV-A1 absorber) and the Tinosorb® M (UV-A1 absorber) were capable of preventing loss of Cn activity when compared to the sunscreens formulations of brand A (low concentration of UV-A1 filters), with the Garcinia brasiliensis extract (UV-B absorber) and with the unprotected cell lysate and exposed to irradiation (Irradiated Control - IC). The Cn activity assay is a reproducible, accurate and selective technique for evaluating the effectiveness of sunscreens against the effects of UV-A1 radiation. The developed method showed that calcineurin activity have the potential to act as a biological indicator of UV-A1 radiation-induced damages in skin and the assay might be used to assess the efficacy of sunscreens agents and plant extracts prior to in vivo tests. Copyright © 2017 Elsevier B.V. All rights reserved.

UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome.

PubMed

Maier, Kristin; He, Yinghong; Wölfle, Ute; Esser, Philipp R; Brummer, Tilman; Schempp, Christoph; Bruckner-Tuderman, Leena; Has, Cristina

2016-12-15

Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus.

PubMed

Zahn, Sabine; Graef, Medina; Patsinakidis, Nikolaos; Landmann, Aysche; Surber, Christian; Wenzel, Joerg; Kuhn, Annegret

2014-07-01

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad-spectrum sunscreen to prevent UV-induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV-dependent activation of interferon (IFN)-driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad-spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen-treated and sunscreen-untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c- and CD123-positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV-irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68-positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN-driven inflammatory response in CLE. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Extract of Punica granatum inhibits skin photoaging induced by UVB irradiation.

PubMed

Park, Hye Min; Moon, Eunjung; Kim, Ae-Jung; Kim, Mi Hyun; Lee, Sanghee; Lee, Jung Bok; Park, Yong Kon; Jung, Hyuk-Sang; Kim, Yoon-Bum; Kim, Sun Yeou

2010-03-01

Punica granatum (pomegranate) is kind of a fruit consumed fresh or in beverage. It has been widely used in traditional medicine in various parts of the world. In this study, we examined the efficacy of a Punica granatum (PG) extract in protecting skin against UVB-induced damage using cultured human skin fibroblasts. A Korean red PG sample was used, and its effects classified according to if the PG source originated from the rind, seed and fruit. The polyphenol content of PG, which is known to prevent other adverse cutaneous effects of UV irradiation, was measured by GC-MS. The protective effects of PG on UVB-induced skin photoaging were examined by determining the level of procollagen type I and MMP-1 after UVB irradiation. Based on the GC-MS quantitative analysis, catechin, quercetin, kaempferol, and equol were the predominant compounds detected in PG. In the changes of expression of procollagen type I and MMP-1 in UV irradiated human skin fibroblasts treated PG, especially extract prepared from rind, the synthesis of collagen was increased and the expression of MMP-1 was decreased. The major polyphenols in PG, particularly catechin, play a significant role in its photoprotective effects on UVB-induced skin damage.

Estimation of risk based on multiple events in radiation carcinogenesis of rat skin

NASA Astrophysics Data System (ADS)

Burns, F. J.; Jin, Y.; Garte, S. J.; Hosselet, S.

1994-10-01

In the multistage theory of carcinogenesis, cells progress to cancer through a series of discrete, irreversible, heritable genetic alterations or mutations. However data on radiation-induced cancer incidence in rat skin suggests that some part of an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to the following radiations: 1. an electron beam (LET = 0.34 keV/um, 2. a neon ion beam (LET = 25 keV/um and 3. an argon ion beam (LET = 125 keV/um. The latter 2 beams were generated by the Bevalac at the Lawrence Berkeley Laboratory, Berkeley, CA. About 6.0 cm2 of skin was irradiated per rat. The rats were observed every 6 weeks for at least 78 weeks and tumors were scored at first occurrence. Several histological types of cancer, including squamous and basal cell carcinomas, were induced. The cancer yield versus radiation dose was fitted by the quadratic equation (Y (D) = CLD + BD2), and the parameters C and B were estimated for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated in all tumors tested, although only a small proportion of neon-induced tumors showed similar activation. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable, linked event pathway at high LET; either pathway may advance the cell by 1 stage in the multistage model. The model, if validated, permits the direct calculation of cancer risk in rat skin in a way that can be subjected to experimental testing.

[UV-irradiation-induced skin cancer as a new occupational disease].

PubMed

Diepgen, T L; Drexler, H; Elsner, P; Schmitt, J

2015-03-01

With the revision of the German Ordinance on Occupational Diseases, skin cancer due to UV irradiation was amended as a new occupational disease to the list of occupational diseases in Germany. The new occupational disease BK 5103 has the following wording: "Squamous cell carcinoma or multiple actinic keratosis of the skin caused by natural UV irradiation". Actinic keratoses are to be considered as multiple according to this new occupational diseases if they occur as single lesions of more than five annually, or are confluent in an area > 4 cm(2) (field cancerization). It is estimated that more than 2.5 million employees are exposed to natural UV irradiation due to their work (outdoor workers) in Germany and therefore have an increased risk of skin cancer. In this article the medical and technical prerequisites which have to be fulfilled for this new occupational disease in Germany are introduced.

Mycosporine-Like Amino Acids: Potential Health and Beauty Ingredients

PubMed Central

Chrapusta, Ewelina; Kaminski, Ariel; Duchnik, Kornelia; Bober, Beata; Adamski, Michal; Bialczyk, Jan

2017-01-01

Human skin is constantly exposed to damaging ultraviolet radiation (UVR), which induces a number of acute and chronic disorders. To reduce the risk of UV-induced skin injury, people apply an additional external protection in the form of cosmetic products containing sunscreens. Nowadays, because of the use of some chemical filters raises a lot of controversies, research focuses on exploring novel, fully safe and highly efficient natural UV-absorbing compounds that could be used as active ingredients in sun care products. A promising alternative is the application of multifunctional mycosporine-like amino acids (MAAs), which can effectively compete with commercially available filters. Here, we outline a complete characterization of these compounds and discuss their enormous biotechnological potential with special emphasis on their use as sunscreens, activators of cells proliferation, anti-cancer agents, anti-photoaging molecules, stimulators of skin renewal, and functional ingredients of UV-protective biomaterials. PMID:29065484

Ultraviolet A within Sunlight Induces Mutations in the Epidermal Basal Layer of Engineered Human Skin

PubMed Central

Huang, Xiao Xuan; Bernerd, Françoise; Halliday, Gary Mark

2009-01-01

The ultraviolet B (UVB) waveband within sunlight is an important carcinogen; however, UVA is also likely to be involved. By ascribing mutations to being either UVB or UVA induced, we have previously shown that human skin cancers contain similar numbers of UVB- and UVA-induced mutations, and, importantly, the UVA mutations were at the base of the epidermis of the tumors. To determine whether these mutations occurred in response to UV, we exposed engineered human skin (EHS) to UVA, UVB, or a mixture that resembled sunlight, and then detected mutations by both denaturing high-performance liquid chromatography and DNA sequencing. EHS resembles human skin, modeling differential waveband penetration to the basal, dividing keratinocytes. We administered only four low doses of UV exposure. Both UVA and UVB induced p53 mutations in irradiated EHS, suggesting that sunlight doses that are achievable during normal daily activities are mutagenic. UVA- but not UVB-induced mutations predominated in the basal epidermis that contains dividing keratinocytes and are thought to give rise to skin tumors. These studies indicate that both UVA and UVB at physiological doses are mutagenic to keratinocytes in EHS. PMID:19264911

Ultraviolet carcinogenesis in the hairless mouse skin. Influence of the sunscreen 2-ethylhexyl-p-methoxycinnamate.

PubMed

Gallagher, C H; Greenoak, G E; Reeve, V E; Canfield, P J; Baker, R S; Bonin, A M

1984-10-01

The mutagenicity of some samples of a commonly used sunscreen, 2-ethylhexyl-p-methoxycinnamate (2-EHMC), led to these studies of its potential carcinogenicity in the HRA/Skh hairless mouse. In a daily treatment regime, repeated for 9 weeks, groups of mice were painted on the dorsum with 2-EHMC, and were then exposed to low doses of one of two artificial ultraviolet (UV) light sources. Mice were also treated with UV alone and with 2-EHMC alone. The accumulated UV exposure alone produced tumours in 40-100% of mice. However, 2-EHMC-treated mice were protected. Subsequent treatment of the 2-EHMC-protected mice, and mice previously treated with 2-EHMC alone, with the tumour promoter, croton oil, produced tumours on a significant number of animals. We conclude that 2-EHMC protects from UV tumorigenesis in the absence of a tumour promoter. However, although tumours appeared on only 4 out of 160 2-EHMC-treated mice exposed to UV, the carcinogenic process had been initiated in others, as application of the tumour promoter, croton oil, produced tumours. Statistical analysis of the incidence of promoted tumours inferred that prior irradiation with UV may not have been implicated. Therefore, 2-EHMC itself may initiate tumours in this strain of hairless mouse.

The injury and cumulative effects on human skin by UV exposure from artificial fluorescence emission.

PubMed

Tian, Yan; Liu, Wei; Niu, TianHui; Dai, CaiHong; Li, Xiaoxin; Cui, Caijuan; Zhao, Xinyan; E, Yaping; Lu, Hui

2014-01-01

The injury and cumulative effects of UV emission from fluorescence lamp were studied. UV intensity from fluorescence lamp was measured, and human skin samples (hips, 10 volunteers) were exposed to low-dose UV irradiation (three times per week for 13 consecutive weeks). Three groups were examined: control group without UV radiation; low-dose group with a cumulative dose of 50 J cm(-2) which was equivalent to irradiation of the face during indoor work for 1.5 years; and high-dose group with 1000 J cm(-2) cumulative dose equivalent to irradiation of the face during outdoor activities for 1 year. Specific indicators were measured before and after UVA irradiation. The findings showed that extending the low-dose UVA exposure decreased the skin moisture content and increased the transepidermal water loss as well as induced skin color changes (decreased L* value, increased M index). Furthermore, irradiated skin showed an increased thickness of cuticle and epidermis, skin edema, light color and unclear staining collagen fibers in the dermis, and elastic fiber fragmentation. In addition, MMP-1, p53 and SIRT1 expression was also increased. Long-term exposure of low-dose UVA radiation enhanced skin photoaging. The safety of the fluorescent lamp needs our attention. © 2014 The American Society of Photobiology.

Parkin regulates translesion DNA synthesis in response to UV radiation

PubMed Central

Huang, Min; Liu, Hongmei; Wang, Fengli; Gong, Juanjuan; Wang, Jiuqiang; Li, Xiaoling; Chen, Qian; Shen, Hongyan; Zhu, Shu; Wang, Yun; Liu, Yang; Guo, Caixia; Tang, Tie-Shan

2017-01-01

Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation. Furthermore, Parkin is found to physically interact with NBS1 (Nijmegen breakage syndrome 1), and to be required for optimal recruitment of NBS1 and DNA polymerase eta (Polη) to UV-induced damage sites. Consequently, depletion of Parkin leads to increased UV-induced mutagenesis. These findings unveil an important role of Parkin in protecting genome stability through positively regulating translesion DNA synthesis (TLS) upon UV damage, providing a novel mechanistic link between Parkin deficiency and predisposition to skin cancers in PD patients. PMID:28430587

Parkin regulates translesion DNA synthesis in response to UV radiation.

PubMed

Zhu, Xuefei; Ma, Xiaolu; Tu, Yingfeng; Huang, Min; Liu, Hongmei; Wang, Fengli; Gong, Juanjuan; Wang, Jiuqiang; Li, Xiaoling; Chen, Qian; Shen, Hongyan; Zhu, Shu; Wang, Yun; Liu, Yang; Guo, Caixia; Tang, Tie-Shan

2017-05-30

Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation. Furthermore, Parkin is found to physically interact with NBS1 (Nijmegen breakage syndrome 1), and to be required for optimal recruitment of NBS1 and DNA polymerase eta (Polη) to UV-induced damage sites. Consequently, depletion of Parkin leads to increased UV-induced mutagenesis. These findings unveil an important role of Parkin in protecting genome stability through positively regulating translesion DNA synthesis (TLS) upon UV damage, providing a novel mechanistic link between Parkin deficiency and predisposition to skin cancers in PD patients.

Effects of Collagen and Collagen Hydrolysate from Jellyfish Umbrella on Histological and Immunity Changes of Mice Photoaging

PubMed Central

Fan, Jian; Zhuang, Yongliang; Li, Bafang

2013-01-01

Jellyfish collagen (JC) was extracted from jellyfish umbrella and hydrolyzed to prepare jellyfish collagen hydrolysate (JCH). The effects of JC and JCH on UV-induced skin damage of mice were evaluated by the skin moisture, microscopic analyses of skin and immunity indexes. The skin moisture analyses showed that moisture retention ability of UV-induced mice skin was increased by JC and JCH. Further histological analysis showed that JC and JCH could repair the endogenous collagen and elastin protein fibers, and could maintain the natural ratio of type I to type III collagen. The immunity indexes showed that JC and JCH play a role in enhancing immunity of photoaging mice in vivo. JCH showed much higher protective ability than JC. These results suggest that JCH as a potential novel antiphotoaging agent from natural resources. PMID:23344251

Antiradiation UV Vaccine: UV Radiation, Biological effects, lesions and medical management - immune-therapy and immune-protection.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Jones, Jeffrey; Maliev, Slava

Key Words: Ultraviolet radiation,Standard Erythema Dose(SED), Minimal Erythema Dose(MED), Sun Burns, Solar Dermatitis, Sun Burned Disease, DNA Damage,Cell Damage, Antiradiation UV Vaccine, Immune-Prophylaxis of Sun Burned Diseases, Immune-Prophylaxis of Sun Burns, Immune-Therapy of Sun-Burned Disease and Sun Burns,Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC), Toxic Epidermal Necrolysis(TEN). Introduction: High doses of UV generated by solar source and artificial sources create an exposure of mammals and other species which can lead to ultraviolet(UV)radiation- associated disease (including erythema, epilation, keratitis, etc.). UV radiation belongs to the non-ionizing part of the electromagnetic spectrum and ranges between 100 nm and 400 nm with 100 nm having been chosen arbitrarily as the boundary between non-ionizing and ionizing radiation, however EMR is a spectrum and UV can produce molecular ionization. UV radiation is conventionally categorized into 3 areas: UV-A (>315-400 nm),UV-B (>280-315 nm)and UV-C (>100-280 nm) [IARC,Working Group Reports,2005] An important consequence of stratospheric ozone depletion is the increased transmission of solar ultraviolet (UV)radiation to the Earth's lower atmosphere and surface. Stratospheric ozone levels have been falling, in certain areas, for the past several decades, so current surface ultraviolet-B (UV-B) radiation levels are thought to be close to their modern day maximum. [S.Madronich et al.1998] Overexposure of ultraviolet radiation a major cause of skin cancer including basal cell carcinoma (BCC), squamous cell carcinoma (SCC) { collectively referred to as “non-melanoma" skin cancer (NMSC) and melanoma as well, with skin cancers being the most common cancer in North America. [Armstrong et al. 1993, Gallagher et al. 2005] Methods and Experimental Design: Our experiments and testing of a novel UV “Antiradiation Vaccine” have employed a wide variety of laboratory animals which include : Chinchilla rabbits, 11-12 months old, live weight 3.5-3.7 (n=11), Balb mice, 2-3 months old, live weight 20-22 g (n=33), Wistar rats, 3-4 months old, live weight 180-220 g(n=33). The studies were approved by the Animal Care and Use Committee for ethical animal research equivalent, at each institution. Seven rabbits, ten mice, eleven Wistar rats were vaccinated with a UV antiradiation vaccine. A second group of animals was used as biological control which received vaccine but no UV Radiation and a third group of animals was used as control without any interventions. Before and after UV Radiation, Vaccination with the UV antiradiation vaccine were provided 17 days prior to UV exposure. The animals were irradiated by a DRT-1 UV generator lamp. The dose of irradiation for laboratory, experimental animals was 10-12 * Standard Erythema Dose (SED) at L=283,7 Laboratory animals were placed in to the box with ventilation. Results: Ultraviolet irradiation of the skin was performed with high doses and causes an inflammation or erythema in all experimental animals. However the grade of skin damage and inflammation was significantly different between animals protected by vaccination and non-protected, non-vaccinated animals. Animals UV-irradiated, but who did not receive the antiradiation vaccine suffered from extensive UV skin burns of second or third degree (grade 2-3). However, animals protected with the UV antiradiation vaccine demonstrated much mild forms of skin cellular injury - mainly erythema, first degree skin burns and a few small patches with second degree skin burns (grade 1-2). Discussion: The severity of skin damage depended on area of exposed skin, time and dose of UV irradiation. Skin injury could be divided into 4 major grades: 1. Faint erythema with dry desquamation. 2. Moderate to severe erythema. 3. Severe erythema with blistering, moist desquamation. 4. Toxic epidermal necrolysis. Mild doses of UV radiation and ionizing radiation can induce cell death by apoptosis and moderate and high doses of UV and ionizing radiation induce cell death by necrosis and generate systemic inflammatory response syndrome (SIRS), toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMODS),and finally, toxic multiple organ failure (TMOF). [D.Popov et al.2012, Fliedner T.et al. 2005, T. Azizova et al. 2004] UV-B is a complete carcinogen that is absorbed by DNA and directly damages DNA. DNA damage induced by UV-B irradiation typically includes the formation of cyclobutane pyrimidine dimmers (CPD) and 6-4 photoproducts (6-4P)[IARC, Working Group Reports, M.Saraiya et al. 2004]. The pre-vaccinated animals seem to have a blunted injury response relative to the unvaccinated animals, presumably by reduction in the inflammatory response and secondary injury effects. The mechanism of action of the antiradiation vaccine, needs further evaluation. Conclusion: A UV antiradiation vaccine appears to demonstrate efficacy as a prophylactic agent for acute solar burns and toxicity. An antiradiation UV vaccine could be used in conjunction with adjunctive measures, e.g. antioxidants and UV barriers to reduce UV radiation toxicity. The authors of this experiments would like to propose further development work of the antiradiation UV vaccine to enhance the armamentarium for prophylaxis and prevention of the various forms skin cancer.

Photo-Oxidation Products of Skin Surface Squalene Mediate Metabolic and Inflammatory Responses to Solar UV in Human Keratinocytes

PubMed Central

Kostyuk, Vladimir; Potapovich, Alla; Stancato, Andrea; De Luca, Chiara; Lulli, Daniela; Pastore, Saveria; Korkina, Liudmila

2012-01-01

The study aimed to identify endogenous lipid mediators of metabolic and inflammatory responses of human keratinocytes to solar UV irradiation. Physiologically relevant doses of solar simulated UVA+UVB were applied to human skin surface lipids (SSL) or to primary cultures of normal human epidermal keratinocytes (NHEK). The decay of photo-sensitive lipid-soluble components, alpha-tocopherol, squalene (Sq), and cholesterol in SSL was analysed and products of squalene photo-oxidation (SqPx) were quantitatively isolated from irradiated SSL. When administered directly to NHEK, low-dose solar UVA+UVB induced time-dependent inflammatory and metabolic responses. To mimic UVA+UVB action, NHEK were exposed to intact or photo-oxidised SSL, Sq or SqPx, 4-hydroxy-2-nonenal (4-HNE), and the product of tryptophan photo-oxidation 6-formylindolo[3,2-b]carbazole (FICZ). FICZ activated exclusively metabolic responses characteristic for UV, i.e. the aryl hydrocarbon receptor (AhR) machinery and downstream CYP1A1/CYP1B1 gene expression, while 4-HNE slightly stimulated inflammatory UV markers IL-6, COX-2, and iNOS genes. On contrast, SqPx induced the majority of metabolic and inflammatory responses characteristic for UVA+UVB, acting via AhR, EGFR, and G-protein-coupled arachidonic acid receptor (G2A). Conclusions/Significance Our findings indicate that Sq could be a primary sensor of solar UV irradiation in human SSL, and products of its photo-oxidation mediate/induce metabolic and inflammatory responses of keratinocytes to UVA+UVB, which could be relevant for skin inflammation in the sun-exposed oily skin. PMID:22952984

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

PubMed

Gil da Costa, Rui M; Aragão, Sofia; Moutinho, Magda; Alvarado, Antonieta; Carmo, Diogo; Casaca, Fátima; Silva, Sandra; Ribeiro, Joana; Sousa, Hugo; Ferreira, Rita; Nogueira-Ferreira, Rita; Pires, Maria João; Colaço, Bruno; Medeiros, Rui; Venâncio, Carlos; Oliveira, Maria Manuel; Bastos, Margarida M S M; Lopes, Carlos; Oliveira, Paula A

2017-01-15

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Wild carrot pentane-based fractions suppress proliferation of human HaCaT keratinocytes and protect against chemically-induced skin cancer.

PubMed

Shebaby, Wassim N; Mroueh, Mohamad A; Boukamp, Petra; Taleb, Robin I; Bodman-Smith, Kikki; El-Sibai, Mirvat; Daher, Costantine F

2017-01-10

Previous studies in our laboratory showed that the Lebanese Daucus carota ssp. carota (wild carrot) oil extract possesses in vitro and in vivo anticancer activities. The present study aims to examine the cytotoxic effect of Daucus carota oil fractions on human epidermal keratinocytes and evaluate the chemopreventive activity of the pentane diethyl ether fraction on DMBA/TPA induced skin carcinogenesis in mice. Wild carrot oil extract was chromatographed to yield four fractions (F1, 100% pentane; F2, 50:50 pentane:diethyl ether; F3, 100% diethyl ether; F4 93:7 chloroform:methanol). The cytotoxic effect of fractions (10, 25, 50 and 100 μg/mL) was tested on human epidermal keratinocytes (non-tumorigenic HaCaT cells and tumorigenic HaCaT-ras variants) using WST a ssay. Cell cycle phase distribution of tumorigenic HaCaT-ras variants was determined by flow cytometry post-treatment with F2 fraction. Apoptosis related proteins were also assessed using western blot. The antitumor activity of F2 fraction was also evaluated using a DMBA/TPA induced skin carcinoma in Balb/c mice. All fractions exhibited significant cytotoxicity, with HaCaT cells being 2.4-3 times less sensitive than HaCaT-ras A5 (benign tumorigenic), and HaCaT-ras II4 (malignant) cells. GC-MS analysis revealed the presence of a major compound (around 60%) in the pentane/diethylether fraction (F2), identified as 2-himachalen-6-ol. Treatment of HaCaT-ras A5 and HaCaT-ras II4 cells with F2 fraction resulted in the accumulation of cells in the sub-G1 apoptotic phase and decreased the population of cells in the S and G2/M phases. Additionally, F2 fraction treatment caused an up-regulation of the expression of pro-apoptotic (Bax) and down-regulation of the expression of anti-apoptotic (Bcl2) proteins. A decrease in the phosphorylation of AKT and ERK was also observed. Intraperitoneal treatment with F2 fraction (50 or 200 mg/kg) in the DMBA/TPA skin carcinogenesis mouse model showed a significant inhibition of papilloma incidence (mice with papilloma), yield (number of papilloma/mouse) and volume (tumor relative size) at weeks 15, 18 and 21. The present data reveal that F2 fraction has a remarkable antitumor activity against DMBA/TPA-induced skin carcinogenesis, an effect that may be mediated through inhibition of the MAPK/ERK and PI3K/AKT pathways.

UV-induced occupational skin cancer: possibilities of secondary individual prevention in the "Dermatologist's Procedure".

PubMed

Elsner, Peter; Blome, Otto; Diepgen, Thomas Ludwig

2013-07-01

Invasive squamous cell carcinoma (SCC) as a "quasi occupational disease" according to §9 Section 2 of the German Social Code Book (SGB) VII typically develops on chronically UV-damaged skin from actinic keratoses. After the Medical Scientific Committee of the Federal Ministry of Labor and Social Affairs has confirmed the legal criteria for acknowledging UV-induced SCC as an occupational disease, it is expected that the condition will be added to the official list of occupational diseases issued by the Federal Government in the near future. The Social Accident Insurance is required by law (§3 Occupational Disease Regulation) to prevent these tumors by "all appropriate means". There are excellent therapeutic and preventive measures for the management of actinic keratoses to avoid the development of SCC. The "Dermatologist's Procedure" according to §§ 41-43 of the agreement between the Social Accident Insurance and the Federal Medical Association was established in Germany in 1972 to take preventive measures in insured persons with skin lesions possibly developing into an occupational disease, or worsening it, or leading to a recurrence of it This procedure proved to be very successful in the prevention of severe and/or recurring skin diseases forcing a worker to leave his job. On the basis of this agreement, the Social Accident Insurance has the instruments to independently provide preventive measures for the new occupational skin disease SCC induced by natural UV light according to §9 Section 2 of the German Social Code Book (SGB) VII. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

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

PubMed

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.

Ultraviolet- and infrared-induced 11 beta-hydroxysteroid dehydrogenase type 1 activating skin photoaging is inhibited by red ginseng extract containing high concentration of ginsenoside Rg3(S).

PubMed

Nam, Jin-Ju; Min, Ji-Eun; Son, Min-Ho; Oh, Jin-Hwan; Kang, Seunghyun

2017-11-01

Sun irradiation is one of major extrinsic stressors responsible for premature skin aging through activation and expression of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol. The aim of this study was to evaluate the inhibitory effects of red ginseng extract containing high concentrations of ginsenoside Rg3 (S) (GERg3) on 11β-HSD1-induced skin photoaging. To evaluate the inhibitory effects of GERg3 on ultraviolet- (UV) or infrared (IR)-induced skin photoaging, human dermal fibroblasts or a normal human 3D skin model was exposed to UV or an IR. RT-PCR, ELISA, Western blot, and H&E staining were used for evaluations. GERg3 was isolated from crude red ginseng. GERg3 inhibited the increased expressions of 11β-HSD1, interleukin (IL)-6, and matrix metalloproteinase-1 (MMP-1) in UVB- or IR-exposed Hs68 cells. Additionally, the increased cortisol, IL-6, and MMP-1 expressions were effectively reduced by GERg3 in UVA-exposed 3D skin models. The photoinduced decrease in type 1 procollagen also recovered as a result of GERg3 treatment in Hs68 cells and the 3D skin model. In addition, the UVA-exposed dermal thickness was decreased in comparison with the UVA-protected 3D skin model, recovered with GERg3 treatment. GERg3 had antiphotoaging effects in UV- or IR-exposed human dermal fibroblasts and normal human 3D skin model. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

UVA-UVB Photoprotective Activity of Topical Formulations Containing Morinda citrifolia Extract

PubMed Central

Serafini, Mairim Russo; Detoni, Cassia Britto; Menezes, Paula dos Passos; Pereira Filho, Rose Nely; Fortes, Vanessa Silveira; Vieira, Maria José Fonseca; Guterres, Sílvia Stanisçuaski; de Albuquerque Junior, Ricardo Luiz Cavalcanti; Araújo, Adriano Antunes de Souza

2014-01-01

Exposure to solar radiation, particularly its ultraviolet (UV) component, has a variety of harmful effects on human health. Some of these effects include sunburn cell formations, basal and squamous cell cancers, melanoma, cataracts, photoaging of the skin, and immune suppression. The beneficial photoprotective effects of topical formulations with the extract, Morinda citrifolia, have not been investigated. This present study aims to investigate the potential benefits of M. citrifolia topical application on the dorsal skin of mice, exposed to UVA-UVB light. Using 7 days of treatment, [before (baseline values) and 20 h after UV exposure], the thickness, skin barrier damage (TEWL), erythema, and histological alterations were evaluated. The results showed that the formulations containing the extract protected the skin against UV-induced damage. PMID:25133171

Genetics of human sensitivity to ultraviolet radiation

NASA Astrophysics Data System (ADS)

Cleaver, James E.

1994-07-01

the major human health effects of solar and artificial UV light occur from the UVB and UVC wavelength ranges and involve a variety of short-term and long-term deleterious changes to the skin and eyes. the more important initial damage to cellular macromolecules involves dimerization of adjacent pyrimidines in DNA to produce cyclobutane pyrimidine dimes, (6-4) pyrimidine- pyrimidone, and (6-4) dewar photoproducts. these photoproducts can be repaired by a genetically regulated enzyme system (nucleotide excision repair) which removes oligonucleotides 29-30 nucleotides long that contain the photoproducts, and synthesizes replacement patches. At least a dozen gene products are involved in the process of recognizing photoproducts in DNA, altering local DNA helicity and cleaving the polynucleotide chain at defined positions either side of a photoproduct. Hereditary mutations in many of these genes are recognized in the human genetic disorders xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Several of the gene products have other functions involving the regulation of gene transcription which accounts for the complex clinical presentation of repair deficient diseases that involve sensitivity of the skin and eyes to UV light, increased solar carcinogenesis (in XP), demyelination, and ganglial calcification (in CS), hair abnormalities (in TTD), and developmental and neurological abnormalities

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis

PubMed Central

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50–555 nmol/ear. PMID:24734106

Inhibitory Effects of Gymnema (Gymnema sylvestre) Leaves on Tumour Promotion in Two-Stage Mouse Skin Carcinogenesis.

PubMed

Yasukawa, Ken; Okuda, Sakiko; Nobushi, Yasuhito

2014-01-01

Ethanol extracts of gymnema (Gymnema sylvestre) leaves exhibited marked antitumour-promoting activity in an in vivo two-stage carcinogenesis test in mice using 7,12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter. From the active fraction of the ethanol extract of the gymnema leaves, three triterpenoids were isolated and identified. These compounds were evaluated for their inhibitory effects on TPA-induced inflammation (1 µg/ear) in mice. The tested compounds showed marked anti-inflammatory effects, with a 50% inhibitory dose of 50-555 nmol/ear.

Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer

PubMed Central

Damiani, Elisabetta; Ullrich, Stephen E.

2016-01-01

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome. PMID:27073146

Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer.

PubMed

Damiani, Elisabetta; Ullrich, Stephen E

2016-07-01

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome. Copyright © 2016 Elsevier B.V. All rights reserved.

Xeroderma Pigmentosum.

PubMed

Black, Jennifer O

2016-06-01

Xeroderma pigmentosum (XP) is a rare disorder of defective UV-radiation induced damage repair that is characterized by photosensitivity with easy skin burning following minimal sun exposure, early freckling and development of lentiginous pigmentation along with other features of poikiloderma and a propensity for developing skin cancer at an early age. In this short review, the clinical, pathological, genetic and molecular aspects of XP are reviewed in the current literature. XP encompasses a spectrum of disease that overlaps with other diseases of DNA repair systems. In addition to cutaneous complications, patients are susceptible to eye conditions, neurodegenerative processes, central nervous system tumors and other tumors as a result of UV radiation exposure and its byproducts. Patients with XP frequently experience a shorter life span due to skin cancer and neurodegenerative sequelae, but aggressive preventative measures to minimize UV radiation exposure and damage can improve the course of disease and prolong life. The disease has served as a model for photoaging and UV radiation-induced cancer and has led to a better understanding of cell processes that prevent development of these disease features in normal individuals.

Multimodal digital color imaging system for facial skin lesion analysis

NASA Astrophysics Data System (ADS)

Bae, Youngwoo; Lee, Youn-Heum; Jung, Byungjo

2008-02-01

In dermatology, various digital imaging modalities have been used as an important tool to quantitatively evaluate the treatment effect of skin lesions. Cross-polarization color image was used to evaluate skin chromophores (melanin and hemoglobin) information and parallel-polarization image to evaluate skin texture information. In addition, UV-A induced fluorescent image has been widely used to evaluate various skin conditions such as sebum, keratosis, sun damages, and vitiligo. In order to maximize the evaluation efficacy of various skin lesions, it is necessary to integrate various imaging modalities into an imaging system. In this study, we propose a multimodal digital color imaging system, which provides four different digital color images of standard color image, parallel and cross-polarization color image, and UV-A induced fluorescent color image. Herein, we describe the imaging system and present the examples of image analysis. By analyzing the color information and morphological features of facial skin lesions, we are able to comparably and simultaneously evaluate various skin lesions. In conclusion, we are sure that the multimodal color imaging system can be utilized as an important assistant tool in dermatology.

In vitro protective effect of a Jacquez grapes wine extract on UVB-induced skin damage.

PubMed

Tomaino, A; Cristani, M; Cimino, F; Speciale, A; Trombetta, D; Bonina, F; Saija, A

2006-12-01

Several studies have shown that UV radiation on the skin results in the formation of reactive oxygen species (ROS) that interact with proteins, lipids and DNA, thus altering cellular functions. The epidermis is composed mainly of keratinocytes, rich in ROS detoxifying enzymes and in low-molecular-mass antioxidant molecules. However, the increased generation of ROS can overwhelm the natural defences against oxidative stress. Therefore treatment of the skin with products containing plant-derived antioxidant ingredients may be a useful strategy for the prevention of UV-mediated cutaneous damage. In the present study we have investigated the in vitro capability of a Jacquez grapes wine extract (containing a significant level of proanthocyanidins, together with lower amounts of anthocyanins and hydroxycinnamic acids; JW-E), to protect skin against UVB-induced oxidative damage by using a three-dimensional tissue culture model of human epidermis. The endpoints of our experiments were cell viability, release of interleukin-1alpha and prostaglandin E(2) (well-known mediators of cutaneous inflammatory processes), accumulation in the epidermis of malondialdehyde/4-hydroxynonenal and protein carbonyl groups (derived by the oxidative damage respectively of lipids and proteins) and tissue redox balance (expressed by the levels of reduced glutathione, oxidized glutathione, glutathione peroxidase and glutathione reductase). Taken together, our findings demonstrate that the JW-E is an efficient botanical mixture able to prevent skin oxidative damage induced by UV-B exposure and may thus be a potential promising candidate as a skin photoprotective agent.

Improvement of polyphenol properties upon glucosylation in a UV-induced skin cell ageing model.

PubMed

Nadim, M; Auriol, D; Lamerant-FayeL, N; Lefèvre, F; Dubanet, L; Redziniak, G; Kieda, C; Grillon, C

2014-12-01

Polyphenols are strong antioxidant molecules allowing prevention of skin photo-ageing damages, but their use is limited due to low solubility and toxicity towards skin cells. We postulated that enzymatic glucosylation could improve their solubility, stability and, consequently, their efficacy. The aim of this work was to study changes induced by addition of a glucose moiety on two polyphenols displaying very different chemical structures [caffeic acid (CA), epigallocatechin-3-gallate (EGCG) and there glucosylated form, Glc-CA and Glc-EGCG] by assessing their cytotoxic properties and their antioxidant and anti-inflammatory activities. Their antioxidant effect was assessed first by the classical DPPH radical-scavenging method. Then, a panel of human skin cells (keratinocytes, melanocytes, fibroblasts and endothelial cells) was used to evaluate their effect on cell toxicity and their antioxidant activities. With this aim, a photo-ageing model based on UV irradiation of skin cells was established. Molecule activity was assessed on reactive oxygen species (ROS) production, on superoxide dismutase (SOD) and catalase activities and, finally, on inflammatory factor production IL-6, IL-8 and IL-1β. In an acellular model, antioxidant activity assessed by DPPH method was strongly reduced for Glc-CA compared to CA, whereas it remained the same for Glc-EGCG compared to EGCG. Glucosylated derivatives did not display more toxic effect on various skin cells. Moreover, toxicity was even strongly reduced for caffeic acid upon glucosylation. The efficacy of glucosyl-compounds against UV-induced ROS production was preserved, both with pre- and post-UV treatments. Particularly, a better antioxidant efficacy was shown by Glc-EGCG, vs. EGCG, on keratinocytes. In addition, an induction of SOD and catalase activity was clearly observed for Glc-CA. Both glucosyl-polyphenols display the same activity as their parent molecule in decreasing inflammatory factor production. Our results demonstrated that enzymatic glucosylation of CA and EGCG led to an improved or preserved antioxidant activity in a cellular model of UV-induced skin ageing, despite the decrease in instantaneous antioxidant properties observed for Glc-CA. Glc-EGCG is specifically more active on keratinocytes, suggesting a specific targeting. Such glucosylated polyphenols displaying improved physicochemical and biological properties should be better candidates than natural ones for use in food additives and cosmetics. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Comparison of skin responses from macroscopic and microscopic UV challenges

NASA Astrophysics Data System (ADS)

Seo, InSeok; Bargo, Paulo R.; Chu, Melissa; Ruvolo, Eduardo; Kollias, Nikiforos

2011-03-01

The minimal erythema dose induced by solar-simulated radiation is a useful measure of UV sensitivity of skin. Most skin phototests have been conducted by projecting a flat field of UV radiation onto the skin in an area greater than 15 cm × 15 cm with an increment of radiation doses. In this study, we investigated the responses of human skin to solar-simulated radiation of different field sizes. Twelve human subjects of skin phototype I-IV were exposed to solar-simulated radiation (SSR) on their upper inner arm or on their lower back with a series of doses in increments of 20% in order to determine the threshold dose to induce a minimal perceptible erythema response (MED). Each dose was delivered with a liquid light guide (8 mm diameter on the back or 6 mm on the upper inner arm) and with quartz optical fibers of 200 μm diameter. The resulting skin responses were evaluated visually and investigated with a reflectance confocal microscope and imaging. The erythema response to the microscopic challenge was always diffuse with no clear boundaries extending to several times the exposed site diameter at doses greater than 2 MED. The skin returned to normal appearance from the microscopic challenge after two weeks of exposure while change in appearance for the larger areas persisted for several weeks to months. This new modality of testing provides the possibility to study skin at the microscopic level with a rapid recovery following challenge.

Ultrastructural demonstration of chemical modification of melanogenesis in hairless mouse skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nishimura, M.; Gellin, G.A.; Hoshino, S.

1982-02-01

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

Solar ultraviolet radiation is necessary to enhance grapevine fruit ripening transcriptional and phenolic responses.

PubMed

Carbonell-Bejerano, Pablo; Diago, Maria-Paz; Martínez-Abaigar, Javier; Martínez-Zapater, José M; Tardáguila, Javier; Núñez-Olivera, Encarnación

2014-07-09

Ultraviolet (UV) radiation modulates secondary metabolism in the skin of Vitis vinifera L. berries, which affects the final composition of both grapes and wines. The expression of several phenylpropanoid biosynthesis-related genes is regulated by UV radiation in grape berries. However, the complete portion of transcriptome and ripening processes influenced by solar UV radiation in grapes remains unknown. Whole genome arrays were used to identify the berry skin transcriptome modulated by the UV radiation received naturally in a mid-altitude Tempranillo vineyard. UV radiation-blocking and transmitting filters were used to generate the experimental conditions. The expression of 121 genes was significantly altered by solar UV radiation. Functional enrichment analysis of altered transcripts mainly pointed out that secondary metabolism-related transcripts were induced by UV radiation including VvFLS1, VvGT5 and VvGT6 flavonol biosynthetic genes and monoterpenoid biosynthetic genes. Berry skin phenolic composition was also analysed to search for correlation with gene expression changes and UV-increased flavonols accumulation was the most evident impact. Among regulatory genes, novel UV radiation-responsive transcription factors including VvMYB24 and three bHLH, together with known grapevine UV-responsive genes such as VvMYBF1, were identified. A transcriptomic meta-analysis revealed that genes up-regulated by UV radiation in the berry skin were also enriched in homologs of Arabidopsis UVR8 UV-B photoreceptor-dependent UV-B -responsive genes. Indeed, a search of the grapevine reference genomic sequence identified UV-B signalling pathway homologs and among them, VvHY5-1, VvHY5-2 and VvRUP were up-regulated by UV radiation in the berry skin. Results suggest that the UV-B radiation-specific signalling pathway is activated in the skin of grapes grown at mid-altitudes. The biosynthesis and accumulation of secondary metabolites, which are appreciated in winemaking and potentially confer cross-tolerance, were almost specifically triggered. This draws attention to viticultural practices that increase solar UV radiation on vineyards as they may improve grape features.

Molecular pathology of skin neoplasms of the head and neck.

PubMed

Kraft, Stefan; Granter, Scott R

2014-06-01

Skin neoplasms include the most common malignancies affecting humans. Many show an ultraviolet (UV)-induced pathogenesis and often affect the head and neck region. To review literature on cutaneous neoplasms that show a predilection for the head and neck region and that are associated with molecular alterations. Literature review. Common nonmelanoma skin cancers, such as basal and squamous cell carcinomas, show a UV-induced pathogenesis. Basal cell carcinomas are characterized by molecular alterations of the Hedgehog pathway, affecting patched and smoothened genes. While squamous cell carcinomas show UV-induced mutations in several genes, driver mutations are only beginning to be identified. In addition, certain adnexal neoplasms also predominantly affect the head and neck region and show interesting, recently discovered molecular abnormalities, or are associated with hereditary conditions whose molecular genetic pathogenesis is well understood. Furthermore, recent advances have led to an increased understanding of the molecular pathogenesis of melanoma. Certain melanoma subtypes, such as lentigo maligna melanoma and desmoplastic melanoma, which are more often seen on the chronically sun-damaged skin of the head and neck, show differences in their molecular signature when compared to the other more common subtypes, such as superficial spreading melanoma, which are more prone to occur at sites with acute intermittent sun damage. In summary, molecular alterations in cutaneous neoplasms of the head and neck are often related to UV exposure. Their molecular footprint often reflects the histologic tumor type, and familiarity with these changes will be increasingly necessary for diagnostic and therapeutic considerations.

Photoprotective effects of topical ginseng leaf extract using Ultraflo L against UVB-induced skin damage in hairless mice.

PubMed

Hong, Yang Hee; Lee, Hyun-Sun; Jung, Eun Young; Han, Sung-Hee; Park, Yooheon; Suh, Hyung Joo

2017-10-01

Abnormal activation of matrix metalloproteinases (MMPs) plays an important role in UV-induced wrinkle formation, which is a major dermatological problem. This formation occurs due to the degeneration of the extracellular matrix (ECM). In this study, we investigated the cutaneous photoprotective effects of Ultraflo L treated ginseng leaf (UTGL) in hairless mice. SKH-1 hairless mice (6 weeks of age) were randomly divided into four groups (8 mice/group). UTGL formulation was applied topically to the skin of the mice for 10 weeks. The normal control group received nonvehicle and was not irradiated with UVB. The UV control (UVB) group received nonvehicle and was exposed to gradient-UVB irradiation. The groups (GA) receiving topical application of UTGL formulation were subjected to gradient-UVB irradiation on 0.5 mg/cm 2 [GA-low (GA-L)] and 1.0 mg/cm 2 [(GA-high (GA-H)] of dorsal skin area, respectively. We found that topical treatment with UTGL attenuated UVB-induced epidermal thickness and impairment of skin barrier function. Additionally, UTGL suppressed the expression of MMP-2, -3, and -13 induced by UVB irradiation. Our results show that topical application of UTGL protects the skin against UVB-induced damage in hairless mice and suggest that UTGL can act as a potential agent for preventing and/or treating UVB-induced photoaging. UTGL possesses sunscreen properties and may exhibit photochemoprotective activities inside the skin of mice. Therefore, UTGL could be used as a potential therapeutic agent to protect the skin against UVB-induced photoaging.

Evaluation of carotenoids and reactive oxygen species in human skin after UV irradiation: a critical comparison between in vivo and ex vivo investigations.

PubMed

Meinke, Martina C; Müller, Robert; Bechtel, Anne; Haag, Stefan F; Darvin, Maxim E; Lohan, Silke B; Ismaeel, Fakher; Lademann, Jürgen

2015-03-01

UV irradiation is one of the most harmful exogenous factors for the human skin. In addition to the development of erythema, free radicals, that is reactive oxygen species (ROS), are induced under its influence and promote the development of oxidative stress in the skin. Several techniques are available for determining the effect of UV irradiation. Resonance Raman spectroscopy (RRS) measures the reduction of the carotenoid concentration, while electron paramagnetic resonance (EPR) spectroscopy enables the analysis of the production of free radicals. Depending on the method, the skin parameters are analysed in vivo or ex vivo. This study provides a critical comparison between in vivo and ex vivo investigations on the ROS formation and carotenoid depletion caused by UV irradiation in human skin. The oxygen content of tissue was also determined. It was shown that the antioxidant status measured in the skin samples in vivo and ex vivo was different. The depletion in the carotenoid concentration in vivo exceeded the value determined ex vivo by a factor of about 1.5, and the radical formation after UV irradiation was significantly greater in vivo by a factor of 3.5 than that measured in excised human skin, which can be explained by the lack of oxygen ex vivo. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protective and therapeutic effects of fucoxanthin against sunburn caused by UV irradiation.

PubMed

Matsui, Mio; Tanaka, Kosuke; Higashiguchi, Naoki; Okawa, Hisato; Yamada, Yoichi; Tanaka, Ken; Taira, Soichiro; Aoyama, Tomoko; Takanishi, Misaki; Natsume, Chika; Takakura, Yuuki; Fujita, Norihisa; Hashimoto, Takeshi; Fujita, Takashi

2016-09-01

Mild exposure to ultraviolet (UV) radiation is also harmful and hazardous to the skin and often causes a photosensitivity disorder accompanied by sunburn. To understand the action of UV on the skin we performed a microarray analysis to isolate UV-sensitive genes. We show here that UV irradiation promoted sunburn and downregulated filaggrin (Flg); fucoxanthin (FX) exerted a protective effect. In vitro analysis showed that UV irradiation of human dermal fibroblasts caused production of intracellular reactive oxygen species (ROS) without cellular toxicity. ROS production was diminished by N-acetylcysteine (NAC) or FX, but not by retinoic acid (RA). In vivo analysis showed that UV irradiation caused sunburn and Flg downregulation, and that FX, but not NAC, RA or clobetasol, exerted a protective effect. FX stimulated Flg promoter activity in a concentration-dependent manner. Flg promoter deletion and chromatin immunoprecipitation analysis showed that caudal type homeo box transcription factor 1 (Cdx1) was a key factor for Flg induction. Cdx1 was also downregulated in UV-exposed skin. Therefore, our data suggested that the protective effects of FX against UV-induced sunburn might be exerted by promotion of skin barrier formation through induction of Flg, unrelated to quenching of ROS or an RA-like action. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Is the current public health message on UV exposure correct?

PubMed Central

Lucas, Robyn M.; Repacholi, Mike H.; McMichael, Anthony J.

2006-01-01

Current sun safety messages stress the importance of sun protection in avoiding the consequences of excessive exposure to ultraviolet radiation (UVR), such as skin cancers, cataracts and other eye diseases, and viral infections caused by UV-induced immunosuppression. However, adequate exposure to UVR has an important role in human health, primarily through UV-induced production of vitamin D, a hormone essential to bone health. Vitamin D insufficiency may be associated with increased risks of some cancers, autoimmune diseases and mental health disorders such as schizophrenia. Here, we review the evolution of current sun exposure practices and sun-safe messages and consider not only the benefits, but also the detrimental effects that such messages may have. UVR-induced vitamin D production can be inhibited by factors such as deep skin pigmentation, indoor lifestyles, older age, sun avoidance behaviours and clothing habits that limit skin exposure, with deleterious consequences for health. There is some early evidence that sun-safe messages are beginning to cause a decrease in skin cancer rates in young people. After the widespread promotion of sun safety, it may now be appropriate to refine public health messages to take better account of variations between groups and their susceptibility to the dangers and benefits of sun exposure. PMID:16799733

Photoprotection beyond ultraviolet radiation--effective sun protection has to include protection against infrared A radiation-induced skin damage.

PubMed

Schroeder, P; Calles, C; Benesova, T; Macaluso, F; Krutmann, J

2010-01-01

Solar radiation is well known to damage human skin, for example by causing premature skin ageing (i.e. photoageing). We have recently learned that this damage does not result from ultraviolet (UV) radiation alone, but also from longer wavelengths, in particular near-infrared radiation (IRA radiation, 760-1,440 nm). IRA radiation accounts for more than one third of the solar energy that reaches human skin. While infrared radiation of longer wavelengths (IRB and IRC) does not penetrate deeply into the skin, more than 65% of the shorter wavelength (IRA) reaches the dermis. IRA radiation has been demonstrated to alter the collagen equilibrium of the dermal extracellular matrix in at least two ways: (a) by leading to an increased expression of the collagen-degrading enzyme matrix metalloproteinase 1, and (b) by decreasing the de novo synthesis of the collagen itself. IRA radiation exposure therefore induces similar biological effects to UV radiation, but the underlying mechanisms are substantially different, specifically, the cellular response to IRA irradiation involves the mitochondrial electron transport chain. Effective sun protection requires specific strategies to prevent IRA radiation-induced skin damage. 2010 S. Karger AG, Basel.

[Photodamage and photoaging--prevention and treatment].

PubMed

Grether-Beck, Susanne; Wlaschek, Meinhard; Krutmann, Jean; Scharffetter-Kochanek, Karin

2005-09-01

The exposure of human skin to environmental and artificial ultraviolet irradiation has increased significantly. This is not only due to an increased solar UV irradiation as a consequence of the stratospheric ozone depletion, but also the result of an inappropriate social behaviour with the use of tanning parlors being very popular. Besides this, leisure activities and living style with travelling to equatorial regions also add to the individual annual UV load. Since the population in industrialised countries shows an increasing total life span, in parallel the cumulative life time dose of solar and artificial UV-irradiation is dramatically augmented. In addition to the common longterm detrimental effects like immunosuppression and skin cancer, the photooxidative damage due to energy absorption of UV photons in an oxygenized environment leads to alterations of cells, subcellular compartments and macromolecules. The clinical manifestations of UV/ROS induced disturbances result in photoaged skin with wrinkle formation, laxity, leathery appearance as well as fragility, impaired wound healing and higher vulnerability. Strategies to prevent or to minimize photoaging and intrinsic aging of the skin necessarily include protection against UV irradiation and antioxidant homoeostasis. New developments of therapeutic interventions including DNA repair enzymes will be discussed.

Protective effects of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin against ultraviolet-induced photodamage in human skin.

PubMed

Oresajo, Christian; Stephens, Thomas; Hino, Peter D; Law, Robert M; Yatskayer, Margarita; Foltis, Peter; Pillai, Sreekumar; Pinnell, Sheldon R

2008-12-01

Ultraviolet (UV) irradiation of the skin leads to acute inflammatory reactions, such as erythema, sunburn, and chronic reactions, including premature skin aging and skin cancer. In this study, the effects of a topical antioxidant mixture consisting of vitamin C, ferulic acid, and phloretin on attenuating the harmful effects of UV irradiation on normal healthy volunteers were studied using biomarkers of skin damage. Ten subjects (age, 18-60 years; Fitzpatrick skin types II and III) were randomized and treated with antioxidant product or vehicle control on the lower back for four consecutive days. On day 3, the minimal erythema dose (MED) was determined for each subject at a different site on the back. On day 4, the two test sites received solar-simulated UV irradiation 1-5x MED at 1x MED intervals. On day 5, digital images were taken, and 4-mm punch biopsies were collected from the two 5x MED test sites and a control site from each subject for morphology and immunohistochemical studies. UV irradiation significantly increased the erythema of human skin in a linear manner from 1x to 5x MED. As early as 24 h after exposure to 5x MEDs of UV irradiation, there were significant increases in sunburn cell formation, thymine dimer formation, matrix metalloproteinase-9 expression, and p53 protein expression. All these changes were attenuated by the antioxidant composition. UV irradiation also suppressed the amount of CD1a-expressing Langerhans cells, indicating immunosuppressive effects of a single 5x MED dose of UV irradiation. Pretreatment of skin with the antioxidant composition blocked this effect. This study confirms the protective role of a unique mixture of antioxidants containing vitamin C, ferulic acid, and phloretin on human skin from the harmful effects of UV irradiation. Phloretin, in addition to being a potent antioxidant, may stabilize and increase the skin availability of topically applied vitamin C and ferulic acid. We propose that antioxidant mixture will complement and synergize with sunscreens in providing photoprotection for human skin.

[Prevention of occupational solar UV radiation-induced epithelial skin cancer].

PubMed

Bauer, A; Beissert, S; Knuschke, P

2015-03-01

Malignancies of the skin, with an incidence of more than 200,000 newly registered cases/year, are the most frequently notified malignances in Germany. In Europe, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) account for about 30 cases/100,000 persons and 50-100 cases/100,000 persons, respectively. Ultraviolet (UV) exposure is the main risk factor to induce these cancers. Increased incidence rates were shown for persons having red/blonde hair as well as light eye colour, acquire sun burns easily, hardly tan and develop freckles. The majority of the malignancies and precursor lesions are acquired by UV exposure in leisure time. However, in highly occupationally UV-exposed outdoor workers, UV monitoring revealed that exposure levels are 2-3 times higher compared to the general population. Occupations likely to be highly exposed are farmers, forestry workers, gardeners, landscapers, fishermen and seafarers, construction workers, builders, tin smiths, sport teachers, mountain guides, etc. Recent metaanalyses showed that occupational UV exposure is a relevant and independent risk factor for SCC and to a lesser extent also for BCC. To prevent occupationally caused malignancies of the skin a significant reduction of occupationally acquired UV dosages in outdoor workers is mandatory. Relevant factors influencing the cumulative sun exposure in outdoor workers are the amount of UV exposure, the specific tasks to be performed in the sun as well as the UV protection habits of the workers. Besides adequate behavior, textile protection by headgear and clothing as well as the regular use of sunscreens and sun glasses are important.

Tannic acid mitigates the DMBA/croton oil-induced skin cancer progression in mice.

PubMed

Majed, Ferial; Rashid, Summya; Khan, Abdul Quaiyoom; Nafees, Sana; Ali, Nemat; Ali, Rashid; Khan, Rehan; Hasan, Syed Kazim; Mehdi, Syed Jafar; Sultana, Sarwat

2015-01-01

Skin cancer is the most common malignancy in the world and also one of the major causes of death worldwide. The toxic environmental pollutant 7,12-dimethylbenz[a]anthracene (DMBA) is a skin-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemical-induced toxicities and carcinogenesis as well. In the present study, we have evaluated the therapeutic potential of tannic acid in DMBA + croton oil-induced skin cancer in Swiss albino mice. Protective effect of TA against skin cancer was evaluated in terms of antioxidant enzymes activities, lipid peroxidation, histopathological changes and expression of inflammation and early tumour markers. DMBA + croton oil causes depletion of antioxidant enzymes (p < 0.001) and elevation of early inflammatory and tumour promotional events. TA prevents the DMBA + croton oil-induced toxicity through a protective mechanism that involves the reduction of oxidative stress as well as COX-2, i-NOS, PCNA protein expression and level of proinflammatory cytokine such as IL-6 release at a very significant level (p < 0.001). It could be concluded from our results that TA attenuates DMBA + croton oil-induced tumour promotional potential possibly by inhibiting oxidative and inflammatory responses and acts as antioxidant, anti-inflammatory and antiproliferative agent.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharma, Som D.; Katiyar, Santosh K., E-mail: skatiyar@uab.ed; Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294

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

Effects of UV Rays and Thymol/Thymus vulgaris L. Extract in an ex vivo Human Skin Model: Morphological and Genotoxicological Assessment.

PubMed

Cornaghi, Laura; Arnaboldi, Francesca; Calò, Rossella; Landoni, Federica; Baruffaldi Preis, William Franz; Marabini, Laura; Donetti, Elena

2016-01-01

Ultraviolet (UV) radiation is the major environmental factor affecting functions of the skin. Compounds rich in polyphenols, such as Thymus vulgaris leaf extract and thymol, have been proposed for the prevention of UV-induced skin damage. We compared the acute effects induced by UVA and UVB rays on epidermal morphology and proliferation, cytotoxicity, and genotoxicity. Normal human skin explants were obtained from young healthy women (n = 7) after informed consent and cultured at the air-liquid interface overnight. After 24 h, the samples were divided in 2 groups: the former exposed to UVA (16 or 24 J/cm2) and the latter irradiated with UVB (0.24 or 0.72 J/cm2). One hour after the end of irradiation, supernatants were collected for evaluation of the lactate dehydrogenase activity. Twenty-four hours after UVB exposure, biopsies were processed for light and transmission electron microscopy analysis, proliferation, cytotoxicity, and genotoxicity. UVB and UVA rays induced early inhibition of cell proliferation and DNA damage compared to controls. In particular, UVB rays were always more cytotoxic and genotoxic than UVA ones. For this reason, we evaluated the effect of either T. vulgaris L. extract (1.82 µg/ml) or thymol (1 µg/ml) on all samples treated for 1 h before UVB irradiation. While Thymus had a protective action for all of the endpoints evaluated, the action of the extract was less pronounced on epidermal proliferation and morphological features. The results presented in this study could be the basis for investigating the mechanism of thymol and T. vulgaris L. extract against the damage induced by UV radiation. © 2016 S. Karger AG, Basel.

Assessment of Augmented Immune Surveillance and Tumor Cell Death by Cytoplasmic Stabilization of p53 as a Chemopreventive Strategy of 3 Promising Medicinal Herbs in Murine 2-Stage Skin Carcinogenesis.

PubMed

Ali, Farrah; Khan, Rehan; Khan, Abdul Quaiyoom; Lateef, Md Abdul; Maqbool, Tahir; Sultana, Sarwat

2014-07-01

Cancer is the final outcome of a plethora of events. Targeting the proliferation or inducing programmed cell death in a proliferating population is a major standpoint in the cancer therapy. However, proliferation is regulated by several cellular and immunologic processes. This study reports the inhibition of proliferation by augmenting immune surveillance, silencing acute inflammation, and inducing p53-mediated apoptosis of skin cancer by 3 promising medicinal extracts. We used the well-characterized model for experimental skin carcinogenesis in mice for 32 weeks to study the chemopreventive effect of the methanolic extracts of Trigonella foenumgraecum, Eclipta alba, and Calendula officinalis. All 3 extracts reduced the number, incidence, and multiplicity of tumors, which was confirmed by the pathologic studies that showed regressed tumors. There was a significant reduction in the PCNA+ nuclei in all treatment groups 32 weeks after the initiation. Mechanistic studies revealed that proliferative population in tumors is diminished by the restoration of the endogenous antioxidant defense, inhibition of the stress-related signal-transducing element NFκB, reduction of inflammation, enhancement of immunosurveillance of the genetically mutated cells, along with silencing of the cell cycle progression signals. Finally, all 3 medicinal extracts induced stable expression of p53 within the tumors, confirmed by the CFDA-Cy3 apoptosis assay. Results of our study confirm that these extracts not only limit the rate of proliferation by inhibition of the processes integral to cancer development but also induce stable cytoplasmic expression of p53-mediated apoptosis, leading to fewer and regressed tumors in mice. © The Author(s) 2013.

Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis.

PubMed

Qi, Cuiling; Lan, Haimei; Ye, Jie; Li, Weidong; Wei, Ping; Yang, Yang; Guo, Simei; Lan, Tian; Li, Jiangchao; Zhang, Qianqian; He, Xiaodong; Wang, Lijing

2014-07-01

Slit, a neuronal guidance cue, binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit has been reported to have an important effect on tumor growth and metastasis. In the current study, we evaluated the role of Slit2 in skin tumor growth and invasion in mice using a two-step chemical carcinogenesis protocol. We found that Slit2 expression correlated with the loss of basement membrane in the samples of human skin squamous cell carcinoma at different stages of disease progression. Slit2-Tg mice developed significantly more skin tumors than wild-type mice. Furthermore, the skin tumors that occurred in Slit2-Tg mice were significantly larger than those in the wild-type mice 10 weeks after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment. We also found that pathological development of the wild-type mice was delayed compared with that of Slit2-Tg mice. To further investigate the mechanism of increasing tumors in Slit2-Tg mice, we analyzed the expression of 5-bromo-2'-deoxyuridine (BrdU) in mouse skin lesions and found that the number of BrdU-positive cells and microvessel density in skin lesions were significantly higher in Slit2-Tg mice than in wild-type mice. Histological staining of PAS and type IV collagen and the colocalization of Slit2 and type IV collagen demonstrated varying degrees of loss of the basement membrane in the skin lesions from Slit2-Tg mice that were at the stage of carcinoma in situ. However, the basement membrane was well defined in the wild-type mice. In addition, MMP2, but not MMP9, was upregulated in the skin tissue of Slit2-Tg mice. Interruption of Slit2-Robo1 signaling by the antibody R5 significantly repressed the invasive capability of the squamous cell carcinoma cell line A431. Taken together, our findings reveal that Slit2 promotes DMBA/TPA-induced skin tumorigenesis by increasing cell proliferation, microvessel density, and invasive behavior of cutaneous squamous cell carcinoma, along with loss of basement membrane, by upregulation of MMP2 expression.

Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53.

PubMed

Page, Angustias; Navarro, Manuel; Suarez-Cabrera, Cristian; Alameda, Josefa P; Casanova, M Llanos; Paramio, Jesús M; Bravo, Ana; Ramirez, Angel

2016-04-12

p53 is a protein that causes cell cycle arrest, apoptosis or senescence, being crucial in the process of tumor suppression in several cell types. Different in vitro and animal models have been designed for the study of p53 role in skin cancer. These models have revealed opposing results, as in some experimental settings it appears that p53 protects against skin cancer, but in others, the opposite conclusion emerges. We have generated cohorts of mice with efficient p53 deletion restricted to stratified epithelia and control littermates expressing wild type p53 and studied their sensitivity to both chemically-induced and spontaneous tumoral transformation, as well as the tumor types originated in each experimental group. Our results indicate that the absence of p53 in stratified epithelia leads to the appearance, in two-stage skin carcinogenesis experiments, of a higher number of tumors that grow faster and become malignant more frequently than tumors arisen in mice with wild type p53 genotype. In addition, the histological diversity of the tumor type is greater in mice with epidermal p53 loss, indicating the tumor suppressive role of p53 in different epidermal cell types. Aging mice with p53 inactivation in stratified epithelia developed spontaneous carcinomas in skin and other epithelia. Overall, these results highlight the truly protective nature of p53 functions in the development of cancer in skin and in other stratified epithelia.

Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komissarova, Elena V.; Rossman, Toby G., E-mail: toby.rossman@nyumc.or

2010-03-15

Arsenite is an environmental pollutant. Exposure to inorganic arsenic in drinking water is associated with elevated cancer risk, especially in skin. Arsenite alone does not cause skin cancer in animals, but arsenite can enhance the carcinogenicity of solar UV. Arsenite is not a significant mutagen at non-toxic concentrations, but it enhances the mutagenicity of other carcinogens. The tumor suppressor protein P53 and nuclear enzyme PARP-1 are both key players in DNA damage response. This laboratory demonstrated earlier that in cells treated with arsenite, the P53-dependent increase in p21{sup WAF1/CIP1} expression, normally a block to cell cycle progression after DNA damage,more » is deficient. Here we show that although long-term exposure of human keratinocytes (HaCaT) to a nontoxic concentration (0.1 muM) of arsenite decreases the level of global protein poly(ADP-ribosyl)ation, it increases poly(ADP-ribosyl)ation of P53 protein and PARP-1 protein abundance. We also demonstrate that exposure to 0.1 muM arsenite depresses the constitutive expression of p21 mRNA and P21 protein in HaCaT cells. Poly(ADP-ribosyl)ation of P53 is reported to block its activation, DNA binding and its functioning as a transcription factor. Our results suggest that arsenite's interference with activation of P53 via poly(ADP-ribosyl)ation may play a role in the comutagenic and cocarcinogenic effects of arsenite.« less

Protective effects of platinum nanoparticles against UV-light-induced epidermal inflammation.

PubMed

Yoshihisa, Yoko; Honda, Ayumi; Zhao, Qing-Li; Makino, Teruhiko; Abe, Riichiro; Matsui, Kotaro; Shimizu, Hiroshi; Miyamoto, Yusei; Kondo, Takashi; Shimizu, Tadamichi

2010-11-01

Intracellular reactive oxygen species (ROS) and apoptosis play important roles in the ultraviolet (UV)-induced inflammatory responses in the skin. Metal nanoparticles have been developed to increase the catalytic activity of metals, which is because of the large surface area of smaller particles. Platinum nanoparticles (nano-Pt) protected by poly acrylic acid were manufactured by reduction with ethanol. A marked increase in ROS production was observed in UV-treated HaCaT keratinocytes cell lines, while a decrease in ROS production was observed in nano-Pt-treated cells. Pretreatment of the cells with nano-Pt also caused a significant inhibition of UVB- and UVC-induced apoptosis. Furthermore, we found that mice treated with nano-Pt gel prior to UV irradiation showed significant inhibition of UVB-induced inflammation and UVA-induced photoallergy compared to UV-irradiated control mice. These results suggest that nano-Pt effectively protects against UV-induced inflammation by decreasing ROS production and inhibiting apoptosis in keratinocytes. © 2010 John Wiley & Sons A/S.

IL-13 but not IL-4 signaling via IL-4Rα protects mice from papilloma formation during DMBA/TPA two-step skin carcinogenesis

PubMed Central

Rothe, Michael; Quarcoo, David; Chashchina, Anna A; Bozrova, Svetlana V; Qin, Zhihai; Nedospasov, Sergei A; Blankenstein, Thomas; Kammertoens, Thomas; Drutskaya, Marina S

2013-01-01

Interleukin 4 (IL-4) was shown to be tumor-promoting in full carcinogenesis studies using 3-methylcholanthrene (MCA). Because heretofore the role of IL-4 in DMBA/TPA (9,10-dimethyl-1,2-benz-anthracene/12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis was not studied, we performed such experiments using either IL-4−/− or IL-4Rα−/− mice. We found that IL-4Rα−/− but not IL-4−/− mice have enhanced papilloma formation, suggesting that IL-13 may be involved. Indeed, IL-13−/− mice developed more papillomas after exposure to DMBA/TPA than their heterozygous IL-13-competent littermate controls. However, when tested in a full carcinogenesis experiment, exposure of mice to 25 μg of MCA, both IL-13−/− and IL-13+/− mice led to the same incidence of tumors. While IL-4 enhances MCA carcinogenesis, it does not play a measurable role in our DMBA/TPA carcinogenesis experiments. Conversely, IL-13 does not affect MCA carcinogenesis but protects mice from DMBA/TPA carcinogenesis. One possible explanation is that IL-4 and IL-13, although they share a common IL-4Rα chain, regulate signaling in target cells differently by employing distinct JAK/STAT-mediated signaling pathways downstream of IL-13 or IL-4 receptor complexes, resulting in different inflammatory transcriptional programs. Taken together, our results indicate that the course of DMBA/TPA- and MCA-induced carcinogenesis is affected differently by IL-4 versus IL-13-mediated inflammatory cascades. PMID:24403255

Ursolic Acid-Regulated Energy Metabolism—Reliever or Propeller of Ultraviolet-Induced Oxidative Stress and DNA Damage?

PubMed Central

Lee, Yuan-Hao; Sun, Youping; Glickman, Randolph D.

2014-01-01

Ultraviolet (UV) light is a leading cause of diseases, such as skin cancers and cataracts. A main process mediating UV-induced pathogenesis is the production of reactive oxygen species (ROS). Excessive ROS levels induce the formation of DNA adducts (e.g., pyrimidine dimers) and result in stalled DNA replication forks. In addition, ROS promotes phosphorylation of tyrosine kinase-coupled hormone receptors and alters downstream energy metabolism. With respect to the risk of UV-induced photocarcinogenesis and photodamage, the antitumoral and antioxidant functions of natural compounds become important for reducing UV-induced adverse effects. One important question in the field is what determines the differential sensitivity of various types of cells to UV light and how exogenous molecules, such as phytochemicals, protect normal cells from UV-inflicted damage while potentiating tumor cell death, presumably via interaction with intracellular target molecules and signaling pathways. Several endogenous molecules have emerged as possible players mediating UV-triggered DNA damage responses. Specifically, UV activates the PIKK (phosphatidylinositol 3-kinase-related kinase) family members, which include DNA-PKcs, ATM (ataxia telangiectasia mutated) and mTOR (mammalian target of rapamycin), whose signaling can be affected by energy metabolism; however, it remains unclear to what extent the activation of hormone receptors regulates PIKKs and whether this crosstalk occurs in all types of cells in response to UV. This review focuses on proteomic descriptions of the relationships between cellular photosensitivity and the phenotypic expression of the insulin/insulin-like growth receptor. It covers the cAMP-dependent pathways, which have recently been shown to regulate the DNA repair machinery through interactions with the PIKK family members. Finally, this review provides a strategic illustration of how UV-induced mitogenic activity is modulated by the insulin sensitizer, ursolic acid (UA), which results in the metabolic adaptation of normal cells against UV-induced ROS, and the metabolic switch of tumor cells subject to UV-induced damage. The multifaceted natural compound, UA, specifically inhibits photo-oxidative DNA damage in retinal pigment epithelial cells while enhancing that in skin melanoma. Considering the UA-mediated differential effects on cell bioenergetics, this article reviews the disparities in glucose metabolism between tumor and normal cells, along with (peroxisome proliferator-activated receptor-γ coactivator 1α)-dependent mitochondrial metabolism and redox (reduction-oxidation) control to demonstrate UA-induced synthetic lethality in tumor cells. PMID:28250388

Microemulsion Using Polyoxyethylene Sorbitan Trioleate and its Usage for Skin Delivery of Resveratrol to Protect Skin against UV-Induced Damage.

PubMed

Yutani, Reiko; Teraoka, Reiko; Kitagawa, Shuji

2015-01-01

We examined the phase behavior of various polyoxyethylene sorbitan fatty acid ester (polysorbates)/ethanol/isopropyl myristate (IPM)/150 mM NaCl solution (NaClaq) systems in order to prepare a microemulsion containing a low ratio of ethanol, which is more suitable for in vivo application. Using polyoxyethylene sorbitan trioleate (Tween 85), which has a large lipophilic moiety, as a surfactant component, single-phase domain of the phase diagram was the largest of all the polysorbates examined, and in particular a large oil-rich single-phase domain was obtained. When the ratio of Tween 85 to ethanol was changed from 1 : 1 to 3 : 1, the oil-rich single-phase domain further expanded, which led to a reduced ethanol concentration in the preparation. Thus, we determined the composition of the microemulsion to be Tween 85 : ethanol : IPM : NaClaq=30 : 10 : 53 : 7, and used it for skin delivery of resveratrol. Microemulsion gel was also prepared by adding 6.5% Aerosil) 200 into the microemulsion for ease of topical application. When applied with each vehicle, delivery of resveratrol into guinea pig skin in vitro was significantly enhanced compared with that by IPM, and resveratrol incorporated into the skin by microemulsion gel decreased lipid peroxidation to 29.5% compared with that of the control. Pretreatment of guinea pig dorsal skin with the microemulsion gel containing resveratrol almost completely prevented UV-B-induced erythema formation in vivo. These findings demonstrate that the microemulsion using Tween 85 containing a minimal concentration of ethanol enhanced the skin delivery of resveratrol and the incorporated resveratrol exhibited a protective effect against UV-induced oxidative damage.

Novel Means for Photoprotection.

PubMed

Sondenheimer, Kevin; Krutmann, Jean

2018-01-01

Due to changes in human lifestyle (expanded sunbathing, the use of solaria, etc.) and, most importantly, increasing lifetime and thus higher cumulative exposure to solar radiation, skin aging and skin cancer have become major health issues. As a consequence effective photoprotection is of outmost importance to humans. In this regard a lot has been learned in the past about the cellular and molecular basis underlying ultraviolet (UV) radiation-induced skin damage and, based on this knowledge, numerous skin protective approaches including organic and inorganic UV-filters, but also topically applicable antioxidants, DNA repair enzymes and compatible solutes as well as oral photoprotective strategies based on nutritional supplements have been developed. A new aspect is here that sun protection of human skin might even be possible after solar radiation-induced skin damage has occurred. A second, very important development was prompted by the discovery that also wavelengths beyond the UV spectrum can damage human skin. These include the blue light region of visible light (VIS) as well as the near infrared range (IRA) and corresponding sunprotection strategies have thus recently been or are still being developed. In this article we will provide a state of the art summary of these two novel developments and, at the end, we will also critically discuss strengths and weaknesses of the current attempts, which mainly focus on the prevention of skin damage by selected wavelengths but greatly ignore the possibility that wavelengths might interfere with each other. Such combined effects, however, need to be taken into account if photoprotection of human skin is intended to be global in nature.

Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice.

PubMed

Lu, Yao-Ping; Lou, You-Rong; Xie, Jian-Guo; Peng, Qing-Yun; Zhou, Sherry; Lin, Yong; Shih, Weichung Joe; Conney, Allan H

2007-01-01

Topical application of caffeine sodium benzoate (caffeine-SB) immediately after UVB irradiation of SKH-1 mice enhanced UVB-induced apoptosis by a 2- to 3-fold greater extent than occurred after the topical application of an equimolar amount of caffeine. Although topical application of caffeine-SB or caffeine enhanced UVB-induced apoptosis, both substances were inactive on non-UVB-treated normal skin. Topical application of caffeine-SB or caffeine (each has UVB absorption properties) 0.5 h before irradiation with a high dose of UVB decreased UVB-induced thymine dimer formation and sunburn lesions (sunscreen effect). Caffeine-SB was more active than an equimolar amount of caffeine in exerting a sunscreen effect. In additional studies, caffeine-SB strongly inhibited the formation of tumors in UVB-pretreated 'high-risk mice' and in tumor-bearing mice, and the growth of UVB-induced tumors was also inhibited. Caffeine-SB and caffeine are the first examples of compounds that have both a sunscreen effect and enhance UVB-induced apoptosis. Our studies suggest that caffeine-SB and caffeine may be good agents for inhibiting the formation of sunlight-induced skin cancer.

[Investigations on the percutaneous activity of a combination of heparin, allantoin and dexpanthenol in a specific ointment base, Antiinflammatory effect on UV-erythema in the guinea pig].

PubMed

Tauschel, H D; Rudolph, C

1982-01-01

Compared to the ointment base, the application of a heparin-allantoin-dexpanthenol combination ointment (Hepathrombin ointment) to guinea pigs immediately after as well as 30 and 120 min prior to UV-irradiation effects more rapid regression of the erythema along with a reduction in erythema formation. After a pretreatment of 30 min, the temperature of the erythematous skin is also significantly lower. At a pretreatment of 120 min, no temperature differences can be observed between the ointment groups. This effect might result from a superimposition of the anti-erythematous/antiinflammatory effect of Hepathrombin along with a vasodilation effect on the deeper skin layers. The antiinflammatory effect of Hepathrombin is also discussed in connection with the mechanism of UV-induced erythema. The inhibition of UV-erythema by Hepathrombin underlines the rapid skin penetration of the active substances.

The role of natural and UV-induced skin pigmentation on low-fluence IPL-induced side effects: a randomized controlled trial.

PubMed

Thaysen-Petersen, Daniel; Lin, Jennifer Y; Nash, Jf; Beerwerth, Frank; Wulf, Hans C; Philipsen, Peter A; Haedersdal, Merete

2014-02-01

The risk of adverse skin effects following light-based hair removal is greater in pigmented skin based on the theory of selective photothermolysis. Thus sunlight-induced pigment i.e., facultative pigmentation, increases the risk of adverse skin effects, perhaps disproportionately. The aim of this study was to evaluate the influence of constitutive and facultative skin pigmentation on low-fluence intense pulsed light (IPL)-induced adverse skin effects. Twenty-one subjects with Fitzpatrick skin type II-IV were enrolled. Two buttock blocks were randomized to receive 0 or 8 solar simulated ultraviolet radiation (UVR) exposures of consecutively increasing Standard Erythema Doses (2-4 SED). Each block was subdivided into four sites, randomized to receive IPL of 0, 7, 8, or 10 J/cm(2) , once a week for 3 weeks. Biopsies were taken 16-24 hours after the first IPL exposure and subjects were seen 1 and 4 weeks after the last IPL exposure. Outcome measures were: (i) skin reactions, (ii) pain, (iii) mRNA expression of pigment-markers microphthalmia-associated transcription factor (MITF) and pro-opiomelanocortin (POMC), and (iv) clinical appearance of biopsy wounds. Skin pigmentation increased after UVR (baseline median 13.8%, after UVR 28.1%, P = 0.0001) in all skin types. Subjects reported low pain intensities (median 1.5, scale 0-10) and experienced transient erythema immediately after IPL exposure. No persistent erythema, blisters, crusting, textual, or pigment changes were observed. The risk of erythema and pain intensities increased with IPL dose and skin pigmentation (P < 0.03). There was no difference in pain or skin reactions in skin with similar degree of natural and facultative pigmentation (P ≥ 0.104). Expression of cellular pigment-markers was not influenced by IPL exposure, neither in constitutive nor in facultative pigmented skin. Clinical appearance of biopsy wounds was unaffected by IPL exposure. The prevalence and intensity of low-fluence IPL-induced adverse skin effects depended on IPL dose and skin pigmentation regardless of the origin, i.e., constitutive versus UV induced. © 2013 Wiley Periodicals, Inc.

THE REACTIVE OXYGEN SPECIES (ROS) THEORY OF ARSENIC CARCINOGENESIS

EPA Science Inventory

Arsenic is a human carcinogen in skin, lung, liver, urinary bladder
and kidney. At this time, there is not a scientific consensus on the
mechanisms/modes of action for arsenic carcinogenesis. Proposed
mechanisms/modes of action for arsenic carcinogenesi...

Dual-Prevention for UV-Induced Skin Damage: Incorporation of Melatonin-Loaded Elastic Niosomes into Octyl Methoxycinnamate Pickering Emulsions.

PubMed

Arslan Azizoglu, Gulcin; Tuncay Tanriverdi, Sakine; Aydin Kose, Fadime; Ballar Kirmizibayrak, Petek; Ozer, Ozgen

2017-11-01

Incorporation of antioxidants into sunscreens is a logical approach, yet co-delivery of them with UV filters is a challenge. Here, we purposed a combination therapy, in which the chemical UV filter, octyl methoxycinnamate, was accumulated on upper skin while the antioxidant, melatonin, can penetrate deeper layers to show its effects. Melatonin-loaded elastic niosomes and octyl methoxycinnamate Pickering emulsion were prepared separately. Lyophilized elastic niosomes were dispersed into the Pickering emulsion to prepare the proposed combination formulation. The characterization studies of the formulations revealed that elastic niosomes can be prepared with tunable nanometer sizes, whereas Pickering emulsions can encapsulate the UV filter in micrometer-sized droplets. Melatonin-loaded elastic niosomes prepared with Tween80/Span80 mixture were 146 nm with a PI of 0.438, and 58.42% entrapment efficiency was achieved. The mean diameter size of the combination formulation was 27.8 μm. Ex vivo permeation studies revealed that 7.40% of octyl methoxycinnamate and 58% of melatonin were permeated through the rat skin while 27.6% octyl methoxycinnamate and 37% of melatonin accumulated in the skin after 24 h. Cell culture studies with real-time cell analyzer showed that the proposed formulation consist of melatonin-loaded elastic niosomes and octyl methoxycinnamate Pickering emulsion had no negative effect on the cell proliferation and viability. According to α,α-diphenyl-β-picrylhydrazyl free radical scavenging method, the proposed formulation showed as high antioxidant activity as melatonin itself. It is concluded that the proposed formulation would be a promising dual therapy for UV-induced skin damage with co-delivery strategy.

Antagonist effects of veratric acid against UVB-induced cell damages.

PubMed

Shin, Seoung Woo; Jung, Eunsun; Kim, Seungbeom; Lee, Kyung-Eun; Youm, Jong-Kyung; Park, Deokhoon

2013-05-10

Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human epidermis, resulting in inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effect of UV irradiation is essential. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. The simple phenolic veratric acid (VA, 3,4-dimethoxybenzoic acid) is one of the major benzoic acid derivatives from vegetables and fruits and it also occurs naturally in medicinal mushrooms which have been reported to have anti-inflammatory and anti-oxidant activities. However, it has rarely been applied in skin care. This study, therefore, aimed to explore the possible roles of veratric acid in protection against UVB-induced damage in HaCaT cells. Results showed that veratric acid can attenuate cyclobutane pyrimidine dimers (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by UVB. Furthermore, veratric acid had inhibitory effects on the UVB-induced release of the inflammatory mediators such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of veratric acid on human skin. Overall, results demonstrated significant benefits of veratric acid on the protection of keratinocyte against UVB-induced injuries and suggested its potential use in skin photoprotection.

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

PubMed Central

2014-01-01

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

Quercetin attenuates the development of 7, 12-dimethyl benz (a) anthracene (DMBA) and croton oil-induced skin cancer in mice

PubMed Central

Ali, Huma; Dixit, Savita

2015-01-01

Abstract To evaluate the chemopreventive potential of quercetin in an experimental skin carcinogenesis mouse model. Skin tumor was induced by topical application of 7, 12-dimethyl Benz (a) anthracene (DMBA) and Croton oil in Swiss albino mouse. Quercetin was orally administered at a concentration of 200 mg/kg and 400 mg/kg body weight daily for 16 weeks in mouse to evaluate chemopreventive potential. Skin cancer was assessed by histopathological analysis. We found that quercetin reduced the tumor size and the cumulative number of papillomas. The mean latent period was significantly increased as compared to carcinogen treated controls. Quercetin significantly decreased the serum levels of glutamate oxalate transaminase, glutamate pyruvate transaminase, alkaline phosphatase and bilirubin. It significantly increased the levels of glutathione, superoxide dismutase and catalase. The elevated level of lipid peroxides in the control group was significantly inhibited by quercetin. Futhermore, DNA damage was significantly decreased in quercetin treated mice as compared to DMBA and croton oil treated mice. The results suggest that quercetin exerts chemopreventive effect on DMBA and croton oil induced skin cancer in mice by increasing antioxidant activities. PMID:25859269

Efficacy of marigold extract-loaded formulations against UV-induced oxidative stress.

PubMed

Fonseca, Yris Maria; Catini, Carolina Dias; Vicentini, Fabiana T M C; Cardoso, Juliana Cordeiro; Cavalcanti De Albuquerque Junior, Ricardo Luiz; Vieira Fonseca, Maria José

2011-06-01

The present study investigated the potential use of topical formulations containing marigold extract (ME) (Calendula officinalis extract) against ultraviolet (UV)B irradiation-induced skin damage. The physical and functional stabilities, as well as the skin penetration capacity, of the different topical formulations developed were evaluated. In addition, the in vivo capacity to prevent/treat the UVB irradiation-induced skin damage, in hairless mice, of the formulation with better skin penetration capacity was investigated. All of the formulations were physically and functionally stable. The gel formulation [Formulation 3 (F3)] was the most effective for the topical delivery of ME, which was detected as 0.21 μg/cm(2) of narcissin and as 0.07 μg/cm(2) of the rutin in the viable epidermis. This formulation was able to maintain glutathione reduced levels close to those of nonirradiated animals, but did not affect the gelatinase-9 and myeloperoxidase activities increased by exposure to UVB irradiation. In addition, F3 reduced the histological skin changes induced by UVB irradiation that appear as modifications of collagen fibrils. Therefore, the photoprotective effect in hairless mice achieved with the topical application of ME in gel formulation is most likely associated with a possible improvement in the collagen synthesis in the subepidermal connective tissue. Copyright © 2010 Wiley-Liss, Inc.

SHINING A LIGHT ON XERODERMA PIGMENTOSUM

PubMed Central

DiGiovanna, John J.; Kraemer, Kenneth H.

2012-01-01

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and ultraviolet (UV) induced skin and mucous membrane cancers. Described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations and skin cancer. XP cells were found to have defects in 7 of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta. XP cells are hypersensitive to killing by UV and XP cancers have characteristic “UV signature” mutations. Clinical studies at NIH found a nearly 10,000-fold increase in skin cancer in XP patients under age 20 years demonstrating the substantial importance of DNA repair in cancer prevention in the general population. About 25 % of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism which kills non-dividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy have defects in some of the same genes as XP but they have primary developmental abnormalities without an increase in skin cancer. PMID:22217736

UV irradiation-induced methionine oxidation in human skin keratins: Mass spectrometry-based non-invasive proteomic analysis.

PubMed

Lee, Seon Hwa; Matsushima, Keita; Miyamoto, Kohei; Oe, Tomoyuki

2016-02-05

Ultraviolet (UV) radiation is the major environmental factor that causes oxidative skin damage. Keratins are the main constituents of human skin and have been identified as oxidative target proteins. We have recently developed a mass spectrometry (MS)-based non-invasive proteomic methodology to screen oxidative modifications in human skin keratins. Using this methodology, UV effects on methionine (Met) oxidation in human skin keratins were investigated. The initial screening revealed that Met(259), Met(262), and Met(296) in K1 keratin were the most susceptible oxidation sites upon UVA (or UVB) irradiation of human tape-stripped skin. Subsequent liquid chromatography/electrospray ionization-MS and tandem MS analyses confirmed amino acid sequences and oxidation sites of tryptic peptides D(290)VDGAYMTK(298) (P1) and N(258)MQDMVEDYR(267) (P2). The relative oxidation levels of P1 and P2 increased in a time-dependent manner upon UVA irradiation. Butylated hydroxytoluene was the most effective antioxidant for artifactual oxidation of Met residues. The relative oxidation levels of P1 and P2 after UVA irradiation for 48 h corresponded to treatment with 100mM hydrogen peroxide for 15 min. In addition, Met(259) was oxidized by only UVA irradiation. The Met sites identified in conjunction with the current proteomic methodology can be used to evaluate skin damage under various conditions of oxidative stress. We demonstrated that the relative Met oxidation levels in keratins directly reflected UV-induced damages to human tape-stripped skin. Human skin proteins isolated by tape stripping were analyzed by MS-based non-invasive proteomic methodology. Met(259), Met(262), and Met(296) in K1 keratin were the most susceptible oxidation sites upon UV irradiation. Met(259) was oxidized by only UVA irradiation. Quantitative LC/ESI-SRM/MS analyses confirmed a time-dependent increase in the relative oxidation of target peptides (P1 and P2) containing these Met residues, upon UVA irradiation of isolated human skin. The relative oxidation levels of P1 and P2 along with the current proteomic methodology could be applied to the assessment of oxidative stress levels in skin after exposure to sunlight. Copyright © 2015 Elsevier B.V. All rights reserved.

Protective effect of Ocimum sanctum on 3-methylcholanthrene, 7,12-dimethylbenz(a)anthracene and aflatoxin B1 induced skin tumorigenesis in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rastogi, Shipra; Shukla, Yogeshwer; Paul, Bhola N.

A study on the protective effect of alcoholic extract of the leaves of Ocimum sanctum on 3-mthylcholanthrene (MCA), 7,12-dimethylbenzanthracene (DMBA) and aflatoxin B{sub 1} (AFB{sub 1}) induced skin tumorigenesis in a mouse model has been investigated. The study involved pretreatment of mice with the leaf extract prior to either MCA application or tetradecanoyl phorbol acetate (TPA) treatment in a two-stage tumor protocol viz a viz, DMBA/TPA and AFB1/TPA. The results of the present study indicate that the pretreatment with alcoholic extract of the leaves of O. sanctum decreased the number of tumors in MCA, DMBA/TPA and AFB1/TPA treated mice. Themore » skin tumor induced animals pretreated with alcoholic extract led to a decrease in the expression of cutaneous {gamma}-glutamyl transpeptidase (GGT) and glutathione-S-transferase-P (GST-P) protein. The histopathological examination of skin tumors treated with leaf extract showed increased infiltration of polymorphonuclear, mononuclear and lymphocytic cells, decreased ornithine decarboxylase activity with concomitant enhancement of interleukin-1{beta} (IL-1{beta}) and tumor necrosis factor-{alpha} (TNF-{alpha}) in the serum, implying the in vivo antiproliferative and immunomodulatory activity of leaf extract. The decrease in cutaneous phase I enzymes and elevation of phase II enzymes in response to topical application of leaf extract prior to MCA, AFB1, DMBA/TPA and AFB1/TPA treatment indicate the possibility of impairment in reactive metabolite(s) formation and thereby reducing skin carcinogenicity. Furthermore, pretreatment of leaf extract in the carcinogen induced animals resulted in elevation of glutathione levels and decrease in lipid peroxidation along with heat shock protein expression, indicating a scavenging or antioxidant potential of the extract during chemical carcinogenesis. Thus it can be concluded that leaf extract of O. sanctum provides protection against chemical carcinogenesis in one or more of the following mechanisms: (i) by acting as an antioxidant; (ii) by modulating phase I and II enzymes; (iii) by exhibiting antiproliferative activity.« less

Red grape (Vitis vinifera L.) flavonoids down-regulate collagen type III expression after UV-A in primary human dermal blood endothelial cells.

PubMed

Di Francesco, Serena; Savio, Monica; Bloise, Nora; Borroni, Giovanni; Stivala, Lucia Anna; Borroni, Riccardo G

2018-05-09

Red grape (Vitis vinifera L.) flavonoids including flavan-3-ols (e.g., catechin and epicatechin), flavonols (e.g., quercetin) and anthocyanins (e.g., malvidin) exert anti-inflammatory and antioxidant activities. In the skin they also have a photoprotective action, and their effects have been extensively investigated in keratinocytes, melanocytes and fibroblasts. Despite their known effects also on blood vasculature, little is known on their activities on human dermal blood endothelial cells (HDBECs), which are critically involved in skin homeostasis as well as in the pathogenesis of neoplastic and inflammatory skin diseases. We sought to study the biological effects of selected red grape flavonoids in preventing the consequences of ultraviolet (UV)-A irradiation in vitro. Our results show that red grape flavonoids prevent UV-A-induced sICAM-1 release in HDBECs, suggesting that this cell type could represent an additional target of the anti-inflammatory activity of flavonoids. In addition, flavonoids effectively inhibited UV-A-induced synthesis of collagen type III at both RNA and protein level, indicating that dermal blood microvasculature could be actively involved in ECM remodelling as a consequence of skin photo-ageing, and that this can be prevented by red grape flavonoids. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

p-Coumaric Acid Attenuates UVB-Induced Release of Stratifin from Keratinocytes and Indirectly Regulates Matrix Metalloproteinase 1 Release from Fibroblasts

PubMed Central

Seok, Jin Kyung

2015-01-01

Ultraviolet (UV) radiation-induced loss of dermal extracellular matrix is associated with skin photoaging. Recent studies demonstrated that keratinocyte-releasable stratifin (SFN) plays a critical role in skin collagen metabolism by inducing matrix metalloproteinase 1 (MMP1) expression in target fibroblasts. In the present study, we examined whether SFN released from UVB-irradiated epidermal keratinocytes increases MMP1 release from dermal fibroblasts, and whether these events are affected by p-coumaric acid (p-CA), a natural phenolic compound with UVB-shielding and antioxidant properties. HaCaT cells were exposed to UVB in the absence and presence of p-CA, and the conditioned medium was used to stimulate fibroblasts in medium transfer experiments. The cells and media were analyzed to determine the expressions/releases of SFN and MMP1. UVB exposure increased SFN release from keratinocytes into the medium. The conditioned medium of UVB-irradiated keratinocytes increased MMP1 release from fibroblasts. The depletion of SFN using a siRNA rendered the conditioned medium of UVB-irradiated keratinocytes ineffective at stimulating fibroblasts to release MMP1. p-CA mitigated UVB-induced SFN expression in keratinocytes, and attenuated the MMP1 release by fibroblasts in medium transfer experiments. In conclusion, the present study demonstrated that the use of UV absorbers such as p-CA would reduce UV-induced SFN-centered signaling events involved in skin photoaging. PMID:25954129

p-Coumaric Acid Attenuates UVB-Induced Release of Stratifin from Keratinocytes and Indirectly Regulates Matrix Metalloproteinase 1 Release from Fibroblasts.

PubMed

Seok, Jin Kyung; Boo, Yong Chool

2015-05-01

Ultraviolet (UV) radiation-induced loss of dermal extracellular matrix is associated with skin photoaging. Recent studies demonstrated that keratinocyte-releasable stratifin (SFN) plays a critical role in skin collagen metabolism by inducing matrix metalloproteinase 1 (MMP1) expression in target fibroblasts. In the present study, we examined whether SFN released from UVB-irradiated epidermal keratinocytes increases MMP1 release from dermal fibroblasts, and whether these events are affected by p-coumaric acid (p-CA), a natural phenolic compound with UVB-shielding and antioxidant properties. HaCaT cells were exposed to UVB in the absence and presence of p-CA, and the conditioned medium was used to stimulate fibroblasts in medium transfer experiments. The cells and media were analyzed to determine the expressions/releases of SFN and MMP1. UVB exposure increased SFN release from keratinocytes into the medium. The conditioned medium of UVB-irradiated keratinocytes increased MMP1 release from fibroblasts. The depletion of SFN using a siRNA rendered the conditioned medium of UVB-irradiated keratinocytes ineffective at stimulating fibroblasts to release MMP1. p-CA mitigated UVB-induced SFN expression in keratinocytes, and attenuated the MMP1 release by fibroblasts in medium transfer experiments. In conclusion, the present study demonstrated that the use of UV absorbers such as p-CA would reduce UV-induced SFN-centered signaling events involved in skin photoaging.

Skin cancer chemoprevention by α-santalol.

PubMed

Zhang, Xiaoying; Dwivedi, Chandradhar

2011-01-01

Alpha-santalol, a naturally occurring terpenoid, has been shown to have chemopreventive effects on both 7, 12-dimethylbenz(a)anthracene (DMBA)-initiated and 12-O- tetradecanoylphorbol-13-acetate (TPA)-promoted skin cancer development in CD-1 and SENCAR mice, and UVB-induced skin cancer developments in SKH-1 hairless mice in a concentration-dependent manner. Studies have demonstrated that α-santalol could be effective against skin carcinogenesis through both induction of apoptosis via caspase activation together with dissipation of mitochondria membrane potential and cytochrome c release in A431 cells, and inhibition of cell growth via induction of G2/M phase arrest in both A431 cells and melanoma UACC-62 cells by altering multiple cell cycle regulatory proteins and complexes. This review summarizes the chemopreventive effects and molecular mechanisms of α-santalol on skin cancer development in both animal models and skin cancer cell lines.

Evaluation of the antioxidant capacity and preventive effects of a topical emulsion and its vehicle control on the skin response to UV exposure.

PubMed

Zhai, H; Behnam, S; Villarama, C D; Arens-Corell, M; Choi, M J; Maibach, H I

2005-01-01

Supplying topical exogenous antioxidants to the skin may prevent or minimize free radical-induced damaging. This study determines antioxidative capacity of a topical skin care emulsion (an oil-in-water vitamin E-containing formulation) versus its vehicle on human skin that was exposed to ultraviolet radiation (UVR) by utilizing a photochemiluminescence device and biophysical methods. Ten healthy Caucasians (3 male and 7 female; mean age 47 +/- 10 years) were enrolled. In a randomized and double-blind manner, a pH-balanced vitamin E emulsion or its vehicle control was applied onto predesignated forearm prior to UVR exposure. Thirty minutes after application, these test sites were exposed to a UV light to induce the minimal erythema dose. One untreated site served as a blank control. Visual scoring and instrumental measurements were recorded at baseline and at 24 h and 48 h thereafter. At day 3, after completing instrumental measurements, each test site was stripped three times in a consecutive manner with a proprietary adhesive tape disc. These tapes were quantified for antioxidant capacity using a photochemiluminescence device. Vitamin E emulsion and vehicle control significantly (p < 0.05) suppressed visual scores when compared with blank control at day 2 and day 3 after UV exposure. However, vitamin E emulsion showed significantly (p < 0.05) lower visual scores when compared with vehicle control at day 2 and day 3 after UV exposure.Also,vitamin E emulsion and its vehicle control significantly (p < 0.05) diminished skin color measurement (a*) values when compared with blank control at day 2 and day 3 after UV exposure. At day 2 after UV exposure, only vitamin E emulsion significantly (p < 0.05) reduced skin blood flow volume when compared with blank control. Vitamin E emulsion and its vehicle control showed significant (p < 0.05) reduction of blood flow volume when compared with blank control at day 3 after UV exposure. Vitamin E emulsion and its vehicle control proved effective in preventing induction of erythema and reducing inflammatory damage caused by UV exposure. The effect of vitamin E emulsion exceeded that of an 'active control'. Copyright 2005 S. Karger AG, Basel

Energy Metabolism Rewiring Precedes UVB-Induced Primary Skin Tumor Formation.

PubMed

Hosseini, Mohsen; Dousset, Léa; Mahfouf, Walid; Serrano-Sanchez, Martin; Redonnet-Vernhet, Isabelle; Mesli, Samir; Kasraian, Zeinab; Obre, Emilie; Bonneu, Marc; Claverol, Stephane; Vlaski, Marija; Ivanovic, Zoran; Rachidi, Walid; Douki, Thierry; Taieb, Alain; Bouzier-Sore, Anne-Karine; Rossignol, Rodrigue; Rezvani, Hamid Reza

2018-06-19

Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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.

PubMed

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.

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

PubMed

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.

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

PubMed Central

Wu, Po-Yuan; Lyu, Jia-Ling; Chien, Ting-Yi; Hsu, Hao-Cheng; Wen, Kuo-Ching

2017-01-01

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. PMID:28994699

(Oncogenic action of ionizing radiation)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1990-01-01

An extensive experiment involving approximately 400 rats exposed to the neon ion beam at the Bevalac in Berkeley, CA and to electrons is nearing completion. The carcinogenicity of energetic electrons was determined for comparison with the neon ion results. As in past reports we will describe progress in three areas corresponding to the specific aims of the proposal: (1) carcinogenesis and DNA strand breaks in rat skin following exposure by the neon ions or electrons; (2) DNA strand breaks in the epidermis as a function of radiation penetration; (3) oncogene activation in radiation-induced rat skin cancers. 72 refs., 6 tabs.

Supplementating with dietary astaxanthin combined with collagen hydrolysate improves facial elasticity and decreases matrix metalloproteinase-1 and -12 expression: a comparative study with placebo.

PubMed

Yoon, Hyun-Sun; Cho, Hyun Hee; Cho, Soyun; Lee, Se-Rah; Shin, Mi-Hee; Chung, Jin Ho

2014-07-01

Photoaging accounts for most age-related changes in skin appearance. It has been suggested that both astaxanthin, a potent antioxidant, and collagen hydrolysate can be used as antiaging modalities in photoaged skin. However, there is no clinical study using astaxanthin combined with collagen hydrolysate. We investigated the effects of using a combination of dietary astaxanthin and collagen hydrolysate supplementation on moderately photoaged skin in humans. A total of 44 healthy subjects were recruited and treated with astaxanthin (2 mg/day) combined with collagen hydrolysate (3 g/day) or placebos, which were identical in appearance and taste to the active supplementation for 12 weeks. The elasticity and hydration properties of facial skin were evaluated using noninvasive objective devices. In addition, we also evaluated the expression of procollagen type I, fibrillin-1, matrix metalloproteinase-1 (MMP-1) and -12, and ultraviolet (UV)-induced DNA damage in artificially UV-irradiated buttock skin before and after treatment. The supplement group showed significant improvements in skin elasticity and transepidermal water loss in photoaged facial skin after 12 weeks compared with the placebo group. In the supplement group, expression of procollagen type I mRNA increased and expression of MMP-1 and -12 mRNA decreased compared with those in the placebo group. In contrast, there was no significant difference in UV-induced DNA damage between groups. These results demonstrate that dietary astaxanthin combined with collagen hydrolysate can improve elasticity and barrier integrity in photoaged human facial skin, and such treatment is well tolerated.

Effect of chemical peeling on the skin in relation to UV irradiation.

PubMed

Funasaka, Yoko; Abdel-Daim, Mohamed; Kawana, Seiji; Nishigori, Chikako

2012-07-01

Chemical peeling is one of the dermatological treatments available for certain cutaneous diseases and conditions or improvement of cosmetic appearance of photoaged skin. However, it needs to be clarified whether the repetitive procedure of chemical peeling on photodamaged skin is safe and whether the different chemicals used for peeling results in similar outcomes or not. In this article, we reviewed the effect of peeling or peeling agents on the skin in relation to ultraviolet (UV) radiation. The pretreatment of peeling agents usually enhance UV sensitivity by inducing increased sunburn cell formation, lowering minimum erythematous dose and increasing cyclobutane pyrimidine dimers. However, this sensitivity is reversible and recovers to normal after 1-week discontinuation. Using animals, the chronic effect of peeling and peeling agents was shown to prevent photocarcinogenesis. There is also an in vitro study using culture cells to know the detailed mechanisms of peeling agents, especially on cell proliferation and apoptotic changes via activating signalling cascades and oxidative stress. It is important to understand the effect of peeling agents on photoaged skin and to know how to deal with UV irradiation during the application of peeling agents and treatment of chemical peeling in daily life. © 2012 John Wiley & Sons A/S.

PTEN positively regulates UVB-induced DNA damage repair

PubMed Central

Ming, Mei; Feng, Li; Shea, Christopher R.; Soltani, Keyoumars; Zhao, Baozhong; Han, Weinong; Smart, Robert C.; Trempus, Carol S.; He, Yu-Ying

2011-01-01

Non-melanoma skin cancer is the most common cancer in the U.S., where DNA-damaging UVB radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared to skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCC, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin, through its ability to positively regulate XPC-dependent GG-NER following DNA damage. PMID:21771908

Malvidin and cyanidin derivatives from açai fruit (Euterpe oleracea Mart.) counteract UV-A-induced oxidative stress in immortalized fibroblasts.

PubMed

Petruk, Ganna; Illiano, Anna; Del Giudice, Rita; Raiola, Assunta; Amoresano, Angela; Rigano, Maria Manuela; Piccoli, Renata; Monti, Daria Maria

2017-07-01

UV-A radiations are known to induce cellular oxidative stress, leading to premature skin aging. Consumption of açai fruit (Euterpe oleracea Martius) is known to have many health benefits due to its high level of antioxidants. Herein, we analyzed the ability of phenolic compounds extracted from this fruit to attenuate UV-A-induced oxidative stress in immortalized fibroblast. A methanol/water açai extract was fractionated by HPLC and each fraction tested for anti-oxidant stress activity. Immortalized fibroblasts were pre-incubated with açai fractions and then exposed to UV-A radiations. Açai extract was found to be able to strongly protect cells from oxidative stress. In particular, reactive oxygen species (ROS) production, GSH depletion, lipid peroxidation and no increase in the phosphorylation levels of proteins involved in the oxidative stress pathway was observed in cells pre-incubated with the extract and then irradiated by UV-A. Mass spectrometry analyses of HPLC fractionated extract led us to the identification of malvidin and cyanidin derivatives as the most active molecules able to counteract the negative effects induced by UV-A irradiation. Our results indicate, for the first time, that açai fruit is a valuable natural source for malvidin and cyanidin to be used as anti-stress molecules and represent good candidates for dietary intervention in the prevention of age related skin damage. Copyright © 2017 Elsevier B.V. All rights reserved.

p53-Regulated Apoptosis Is Differentiation Dependent in Ultraviolet B-Irradiated Mouse Keratinocytes

PubMed Central

Tron, Victor A.; Trotter, Martin J.; Tang, Liren; Krajewska, Maryla; Reed, John C.; Ho, Vincent C.; Li, Gang

1998-01-01

Previous studies from our laboratory, using p53 transgenic mice, have suggested that ultraviolet (UV) light-induced keratinocyte apoptosis in the skin is not affected by overexpression of mutant p53 protein. To further elucidate a possible role for p53 in UV-induced keratinocyte cell death, we now examine apoptosis in skin and isolated keratinocytes from p53 null (−/−) mice and assess the influence of cell differentiation on this process. In vivo, using this knockout model, epidermal keratinocytes in p53−/− mice exhibited only a 5.2-fold increase in apoptosis after 2000 J/m2 UVB irradiation compared with a 26.3-fold increase in normal control animals. If this p53-dependent apoptosis is important in elimination of precancerous, UV-damaged keratinocytes, then it should be active in the undifferentiated cells of the epidermal basal layer. To test this hypothesis, we examined the effect of differentiation on UV-induced apoptosis in primary cultures of murine and human keratinocytes. Apoptosis was p53-independent in undifferentiated murine keratinocytes, which exhibited relative resistance to UVB-induced killing with only a 1.5-fold increase in apoptosis in p53+/+ cells and a 1.4-fold increase in p53−/− cells. Differentiated keratinocytes, in contrast, showed a 9.4-fold UVB induction of apoptosis in p53+/+ cells, almost three times the induction observed in p53−/− cells. This UV-induced difference in apoptosis was observed when keratinocytes were cultured on type IV collagen substrate, but not on plastic alone. Western blotting of UV-irradiated, differentiated keratinocytes did not support a role for either Bax or Bcl-2 in this process. In support of these findings in mice, cell death in human cultured keratinocytes also occurred in a differentiation-associated fashion. We conclude that p53-induced apoptosis eliminates damaged keratinocytes in the differentiated cell compartment, but this mechanism is not active in the basal, undifferentiated cells and is therefore of questionable significance in protection against skin cancer induction. PMID:9708817

Flavonols Protect Against UV Radiation-Induced Thymine Dimer Formation in an Artificial Skin Mimic.

PubMed

Maini, Sabia; Fahlman, Brian M; Krol, Ed S

2015-01-01

Exposure of skin to ultraviolet light has been shown to have a number of deleterious effects including photoaging, photoimmunosuppression and photoinduced DNA damage which can lead to the development of skin cancer. In this paper we present a study on the ability of three flavonols to protect EpiDerm™, an artificial skin mimic, against UV-induced damage. EpiDerm™ samples were treated with flavonol in acetone and exposed to UVA (100 kJ/m(2) at 365 nm) and UVB (9000 J/m(2) at 310 nm) radiation. Secretion of matrix metalloproteinase-1 (MMP-1) and tumor necrosis factor-α (TNF-a) were determined by ELISA, cyclobutane pyrimidine dimers were quantified using LC-APCI-MS. EpiDerm™ treated topically with quercetin significantly decreased MMP-1 secretion induced by UVA (100 µM) or UVB (200 µM) and TNF-a secretion was significantly reduced at 100 µM quercetin for both UVA and UVB radiation. In addition, topically applied quercetin was found to be photostable over the duration of the experiment. EpiDerm™ samples were treated topically with quercetin, kaempferol or galangin (52 µM) immediately prior to UVA or UVB exposure, and the cyclobutane thymine dimers (T-T (CPD)) were quantified using an HPLC-APCI MS/MS method. All three flavonols significantly decreased T-T (CPD) formation in UVB irradiated EpiDerm™, however no effect could be observed for the UVA irradiation experiments as thymine dimer formation was below the limit of quantitation. Our results suggest that flavonols can provide protection against UV radiation-induced skin damage through both antioxidant activity and direct photo-absorption. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Time-dependent effect of rutin on skin fibroblasts membrane disruption following UV radiation.

PubMed

Gęgotek, Agnieszka; Bielawska, Katarzyna; Biernacki, Michał; Dobrzyńska, Izabela; Skrzydlewska, Elżbieta

2017-08-01

Chronic exposure of the skin to solar UV radiation induces a number of biological alterations, including a redox imbalance; therefore, there is an urgent need for skin cells protective compounds. The aim of this study was to determine the effects of natural, previously extensively examined, polyphenol with antioxidant properties - rutin, on UV-induced skin fibroblasts membrane disruption. Accordingly, fibroblasts exposed to UVA and UVB irradiation were incubated with rutin (12h before and/or up to 24h after irradiation), and the structural and metabolic changes were examined. Rutin penetration through the fibroblast phospholipid bilayer was aided by UVA-induced bilitranslocase activity 2-4h after irradiation, while UVB irradiation led to enhanced phospholipid peroxidation and higher membrane permeability to facilitate the interaction of rutin with phospholipids. Lipidomic analysis revealed that 4h of rutin treatment also partially prevented UVA/B-induced increase in phosphatidylethanolamine and phosphatidylcholine level, as well as their membrane localization, which resulted in an enhanced zeta potential in the cells and liposomes. Moreover, rutin 2h following irradiation, in a various degree, prevented the increased in phospholipase A2 activity and ROS generation, and partially protected against the reduction of arachidonic and linoleic acids level and the lipid peroxidation product 4-hydroxynonenal level increase. Rutin effectively prevented against decrease in glutathione peroxidase, glutathione and vitamins E and C activities/levels, particularly 2h following UVA irradiation. In conclusion, highest skin fibroblasts membrane level of rutin occurred in 2-4h following UVA/B-radiation results in its strongest effect on biomembrane structure and functions and cellular antioxidant system irrespective of the radiation type. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Visible Light Induces Melanogenesis in Human Skin through a Photoadaptive Response.

PubMed

Randhawa, Manpreet; Seo, InSeok; Liebel, Frank; Southall, Michael D; Kollias, Nikiforos; Ruvolo, Eduardo

2015-01-01

Visible light (400-700 nm) lies outside of the spectral range of what photobiologists define as deleterious radiation and as a result few studies have studied the effects of visible light range of wavelengths on skin. This oversight is important considering that during outdoors activities skin is exposed to the full solar spectrum, including visible light, and to multiple exposures at different times and doses. Although the contribution of the UV component of sunlight to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology in terms of inflammation, and limited information is available regarding the role of visible light on pigmentation. The purpose of this study was to determine the effect of visible light on the pro-pigmentation pathways and melanin formation in skin. Exposure to visible light in ex-vivo and clinical studies demonstrated an induction of pigmentation in skin by visible light. Results showed that a single exposure to visible light induced very little pigmentation whereas multiple exposures with visible light resulted in darker and sustained pigmentation. These findings have potential implications on the management of photo-aggravated pigmentary disorders, the proper use of sunscreens, and the treatment of depigmented lesions.

Non-invasive high-intensity focused ultrasound for UV-induced hyperpigmentation in Fitzpatrick skin types III and IV: a prospective, randomized, controlled, evaluator-blinded trial.

PubMed

Vachiramon, Vasanop; Jurairattanaporn, Natthachat; Harnchoowong, Sarawin; Chayavichitsilp, Pamela

2018-02-01

Skin hyperpigmentation is a frequently encountered problem, particularly in darker skin types. Unfortunately, standard treatments for this condition have shown disappointing results. High-intensity focused ultrasound (HIFU) is commonly indicated for skin laxity, but recently was used to treat UV-induced hyperpigmentation in animal models. This study is aimed to evaluate the efficacy and safety of high-intensity focused ultrasound for UVB-induced hyperpigmentation in human subjects. A randomized, evaluator-blinded pilot study was conducted on 20 subjects. Each subject was induced three hyperpigmentary spots by local broadband UVB. After 2 weeks, each spot was randomly allocated to control, low-energy, and high-energy HIFU. Subjects were instructed to follow up weekly for a duration of 1 month. Lightness index measurements, mean improvement scores, subjects' satisfaction, pain scores, and side effects were evaluated. All 20 subjects completed the study. Fourteen subjects had Fitzpatrick (FPT) skin type III and six subjects had FPT skin type IV. Twelve subjects showed greater improvement at control sites while eight subjects showed greater improvement at HIFU-treated sites. In FPT skin type III, HIFU appeared to be inferior to control in both lightness index and mean improvement scores, but in FPT skin type IV, HIFU had greater lightness index improvement and higher improvement scores than control. Side effects were more frequent in high-energy-treated areas. Focused ultrasound may be offered in some patients with hyperpigmentary conditions. More research is needed to determine proper energy settings for optimal outcome.

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

PubMed

Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

2012-06-01

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

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

PubMed

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

2014-06-01

Recent studies have demonstrated silibinin efficacy against ultraviolet B (UVB)-induced skin carcinogenesis via different mechanisms in cell lines and animal models; however, its role in regulating interleukin-12 (IL-12), an immunomodulatory cytokine that reduces UVB-induced DNA damage and apoptosis, is not known. Here, we report that UVB irradiation causes caspase 3 and PARP cleavage and apoptosis, and addition of recombinant IL-12 or silibinin immediately after UVB significantly protects UVB-induced apoptosis in JB6 cells. IL-12 antibody-mediated blocking of IL-12 activity compromised the protective effects of both IL-12 and silibinin. Both silibinin and IL-12 also accelerated the repair of UVB-caused cyclobutane-pyrimidine dimers (CPDs) in JB6 cells. Additional studies confirmed that indeed silibinin causes a significant increase in IL-12 levels in UVB-irradiated JB6 cells as well as in mouse skin epidermis, and that similar to cell-culture findings, silibinin topical application immediately after UVB exposure causes a strong protection against UVB-induced TUNEL positive cells in epidermis possibly through a significantly accelerated repair of UVB-caused CPDs. Together, these findings for the first time provide an important insight regarding the pharmacological mechanism wherein silibinin induces endogenous IL-12 in its efficacy against UVB-caused skin damages. In view of the fact that an enhanced endogenous IL-12 level could effectively remove UVB-caused DNA damage and associated skin cancer, our findings suggest that the use of silibinin in UVB-damaged human skin would also be a practical and translational strategy to manage solar radiation-caused skin damages as well as skin cancer. © 2013 Wiley Periodicals, Inc.

DOSE-RESPONSE FOR UV-INDUCED IMMUNE SUPPRESSION IN PEOPLE OF COLOR: DIFFERENCES BASED ON ERYTHEMAL REACTIVITY RATHER THAN SKIN PIGMENTATION

EPA Science Inventory

Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation...

Soft, stretchable, epidermal sensor with integrated electronics and photochemistry for measuring personal UV exposures.

PubMed

Shi, Yunzhou; Manco, Megan; Moyal, Dominique; Huppert, Gil; Araki, Hitoshi; Banks, Anthony; Joshi, Hemant; McKenzie, Richard; Seewald, Alex; Griffin, Guy; Sen-Gupta, Ellora; Wright, Donald; Bastien, Philippe; Valceschini, Florent; Seité, Sophie; Wright, John A; Ghaffari, Roozbeh; Rogers, John; Balooch, Guive; Pielak, Rafal M

2018-01-01

Excessive ultraviolet (UV) radiation induces acute and chronic effects on the skin, eye and immune system. Personalized monitoring of UV radiation is thus paramount to measure the extent of personal sun exposure, which could vary with environment, lifestyle, and sunscreen use. Here, we demonstrate an ultralow modulus, stretchable, skin-mounted UV patch that measures personal UV doses. The patch contains functional layers of ultrathin stretchable electronics and a photosensitive patterned dye that reacts to UV radiation. Color changes in the photosensitive dyes correspond to UV radiation intensity and are analyzed with a smartphone camera. A software application has feature recognition, lighting condition correction, and quantification algorithms that detect and quantify changes in color. These color changes are then correlated with corresponding shifts in UV dose, and compared to existing UV dose risk levels. The soft mechanics of the UV patch allow for multi-day wear in the presence of sunscreen and water. Two evaluation studies serve to demonstrate the utility of the UV patch during daily activities with and without sunscreen application.

Soft, stretchable, epidermal sensor with integrated electronics and photochemistry for measuring personal UV exposures

PubMed Central

Shi, Yunzhou; Manco, Megan; Moyal, Dominique; Huppert, Gil; Araki, Hitoshi; Banks, Anthony; Joshi, Hemant; McKenzie, Richard; Seewald, Alex; Griffin, Guy; Sen-Gupta, Ellora; Wright, Donald; Bastien, Philippe; Valceschini, Florent; Seité, Sophie; Wright, John A.; Ghaffari, Roozbeh; Rogers, John; Balooch, Guive

2018-01-01

Excessive ultraviolet (UV) radiation induces acute and chronic effects on the skin, eye and immune system. Personalized monitoring of UV radiation is thus paramount to measure the extent of personal sun exposure, which could vary with environment, lifestyle, and sunscreen use. Here, we demonstrate an ultralow modulus, stretchable, skin-mounted UV patch that measures personal UV doses. The patch contains functional layers of ultrathin stretchable electronics and a photosensitive patterned dye that reacts to UV radiation. Color changes in the photosensitive dyes correspond to UV radiation intensity and are analyzed with a smartphone camera. A software application has feature recognition, lighting condition correction, and quantification algorithms that detect and quantify changes in color. These color changes are then correlated with corresponding shifts in UV dose, and compared to existing UV dose risk levels. The soft mechanics of the UV patch allow for multi-day wear in the presence of sunscreen and water. Two evaluation studies serve to demonstrate the utility of the UV patch during daily activities with and without sunscreen application. PMID:29293664

Aqueous Extract of Chrysanthemum morifolium ( Jú Huā) Enhances the Antimelanogenic and Antioxidative Activities of the Mixture of Soy Peptide and Collagen Peptide.

PubMed

Gui, Min; Du, Jun; Guo, Jianmin; Xiao, Baiquan; Yang, Wei; Li, Minjie

2014-07-01

The possible synergistic effect between the aqueous extract of Chrysanthemum morifolium ( Jú Huā) (AECM) and the peptide mixture (PM) containing soy peptide and collagen peptide was investigated in an ultraviolet (UV) irradiation-induced skin damage mouse model. The irradiated mice were treated with the PM or PM + AECM (containing PM and AECM), respectively. Both PM and PM + AECM groups displayed an apparent photoprotective effect on the UV-irradiated skin damage of mice. Histological evaluation demonstrated that the epidermal hyperplasia and melanocytes in the basal epidermal layer of the UV-irradiated skin in mice decreased when treated with either PM or PM + AECM. Further study showed that soy peptide, collagen peptide, and AECM also inhibited the activities of mushroom tyrosinase with IC50 values of 82.3, 28.2, and 1.6 μg/ml, respectively. Additionally, PM + AECM reduced melanogenesis by 46.2% at the concentration of 10 mg/ml in B16 mouse melanoma cells. Meanwhile, the UV-induced increase of antioxidative indicators, including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyde (MDA), was reduced significantly after treatment with 1.83 g/kg/dbw of PM + AECM. This evidence supported the synergistic antioxidative effect of AECM with PM. These results demonstrated that oral intake of PM and AECM had synergistic antimelanogenic and antioxidative effects in UV-irradiated mice.

Molecular mechanisms of inhibition of photocarcinogenesis by silymarin, a phytochemical from milk thistle (Silybum marianum L. Gaertn.) (Review).

PubMed

Vaid, Mudit; Katiyar, Santosh K

2010-05-01

Changes in life style over the past several decades including much of the time spent outdoors and the use of tanning devices for cosmetic purposes by individuals have led to an increase in the incidence of solar ultraviolet (UV) radiation-induced skin diseases including the risk of skin cancers. Solar UV radiations are considered as the most prevalent environmental carcinogens, and chronic exposure of the skin to UV leads to squamous and basal cell carcinoma and melanoma in human population. A wide variety of phytochemicals have been reported to have substantial anti-carcinogenic activity because of their antioxidant and anti-inflammatory properties. Silymarin is one of them and extensively studied for its skin photoprotective capabilities. Silymarin, a flavanolignan, is extracted from the fruits and seeds of milk thistle (Silybum marianum L. Gaertn.), and has been shown to have chemopreventive effects against photocarcinogenesis in mouse tumor models. Topical treatment of silymarin inhibited photocarcinogenesis in mice in terms of tumor incidence, tumor multiplicity and growth of the tumors. Wide range of in vivo mechanistic studies conducted in a variety of mouse models indicated that silymarin has anti-oxidant, anti-inflammatory and immunomodulatory properties which led to the prevention of photocarcinogenesis in mice. This review summarizes and updates the photoprotective potential of silymarin with the particular emphasis on its in vivo mechanism of actions. It is suggested that silymarin may favorably supplement sunscreen protection, and may be useful for skin diseases associated with solar UV radiation-induced inflammation, oxidative stress and immunomodulatory effects.

[Impact of the women's press on the attitudes of readers toward ultraviolet radiation--a survey of law and psychology students].

PubMed

Gałajda, Karolina; Kamińska-Winciorek, Grazyna; Spiewak, Radosław

2013-08-01

Excessive exposure to ultraviolet radiation (UVA and UVB) leads to negative consequences including sunburn, carcinogenesis and photoaging. Therefore, educational campaigns promoting safe tanning and sunscreens are necessary. Helpful with this regard might be mass media including women's magazines, which for young people are important source of information on health, beauty and lifestyle. The aim of the study was to examine the influence of women's press in the attitude of non-medical students toward ultraviolet radiation (UV) as well as to analyse articles about tanning and skin protection against UV rays in selected magazines for women. The study group consisted of 68 psychology students and 60 law students (n = 128). An original author's questionnaire was used in this research, including 22 questions regarding frequency of reading articles about sunbathing, and the impact of women's press on the respondents' attitude toward suntanning. In the second part of the study 13 articles were examined from magazines "Twój Styl", "ELLE", "PANI" (years 2007-2011), which contained keywords "sun", "tanning bed", "tanning", "UV radiation". Selected articles were assessed whether they were encouraging to, or discouraging from sunbathing. A majority (63%) of respondents declared that after reading the article in women's magazines, they began to apply a sunscreen with higher SPF rate than before. Moreover, 57% refrained from using tanbeds, and 48% began to regularly check melanocytic naevi and monitor their skin after sun exposures. The analysis of the articles showed that majority of articles discouraged from the sunbathing (11 articles discouraging versus and 2 encouraging). Women's press in Poland generally promotes women's rational behavior against UV radiation and tanning.

Free radicals induced by sunlight in different spectral regions - in vivo versus ex vivo study.

PubMed

Lohan, Silke B; Müller, Robert; Albrecht, Stephanie; Mink, Kathrin; Tscherch, Kathrin; Ismaeel, Fakher; Lademann, Jürgen; Rohn, Sascha; Meinke, Martina C

2016-05-01

Sunlight represents an exogenous factor stimulating formation of free radicals which can induce cell damage. To assess the effect of the different spectral solar regions on the development of free radicals in skin, in vivo electron paramagnetic resonance (EPR) investigations with human volunteers and ex vivo studies on excised human and porcine skin were carried out. For all skin probes, the ultraviolet (UV) spectral region stimulates the most intensive radical formation, followed by the visible (VIS) and the near infrared (NIR) regions. A comparison between the different skin models shows that for UV light, the fastest and highest production of free radicals could be detected in vivo, followed by excised porcine and human skin. The same distribution pattern was found for the VIS/NIR spectral regions, whereby the differences in radical formation between in vivo and ex vivo were less pronounced. An analysis of lipid composition in vivo before and after exposure to UV light clearly showed modifications in several skin lipid components; a decrease of ceramide subclass [AP2] and an increase of ceramide subclass [NP2], sodium cholesterol sulphate and squalene (SQ) were detectable. In contrast, VIS/NIR irradiation led to an increase of ceramides [AP2] and SCS, and a decrease of SQ. These results, which are largely comparable for the different skin models investigated in vivo and ex vivo, indicate that radiation exposure in different spectral regions strongly influences radical production in skin and also results in changes in skin lipid composition, which is essential for barrier function. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Inhibitory effects of dietary Spirulina platensis on UVB-induced skin inflammatory responses and carcinogenesis.

PubMed

Yogianti, Flandiana; Kunisada, Makoto; Nakano, Eiji; Ono, Ryusuke; Sakumi, Kunihiko; Oka, Sugako; Nakabeppu, Yusaku; Nishigori, Chikako

2014-10-01

Reactive oxygen species produced in response to UVR are important in skin tumor development. We have previously reported that deficiency of the Ogg1 gene, encoding the repair enzyme for 8-oxo-7,8-dihydroguanine (8-oxoG), increases skin tumor incidence in mice upon repetitive UVB exposure and modulation of UVB-induced inflammatory response. Spirulina platensis is used as a human food supplement because it contains abundant nutritional and antioxidant components. Therefore, we investigated the inhibitory effects of S. platensis on UVB-induced skin tumor development in Ogg1 knockout-(KO) mice and the wild-type (WT) counterpart. Dietary S. platensis suppressed tumor induction and development in both genotypes compared with our previous data without S. platensis. Induction of erythema and ear swelling, one of the hallmarks of UVB-induced inflammatory responses, was suppressed in the skin of Ogg1-KO mice and albino hairless mice fed with dietary S. platensis. Compared with untreated mice, S. platensis-administered mice showed significantly reduced 8-oxoG formation in the skin after UVB exposure. Moreover, we found that S. platensis effectively downregulated the signal proteins p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and extracellular signal-regulated kinase after UVB exposure especially in Ogg1-KO mice. Our results suggest that S. platensis exerts antitumor effects against UVB irradiation in the skin through its anti-inflammatory and antioxidant effects.

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.

PubMed

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; Shi, Xianglin

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), PGE2 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. Copyright © 2014 Elsevier Inc. All rights reserved.

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

PubMed Central

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; Shi, Xianglin

2015-01-01

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), PGE2 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. PMID:25062774

Cutaneous vitamin D synthesis versus skin cancer development

PubMed Central

Nürnberg, Bernd

2009-01-01

In scientific and public communities, there is an ongoing discussion how to balance between positive and negative effects of solar UV-exposure. On the one hand, solar UV-radiation represents the most important environmental risk factor for the development of non-melanoma skin cancer. Consequently, UV protection is an important measure to prevent these malignancies, especially in risk groups. Otherwise, approximately 90% of all vitamin D needed by the human body has to be formed in the skin through the action of UV-radiation. This dilemma represents a serious problem, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer, bone diseases, autoimmune diseases, infectious diseases, cardiovascular diseases and hypertension has now been reported in a large number of investigative and epidemiologic studies. As a consequence, it has been assumed that for the general population in the US, Europe and other countries, the net effects of solar UV B-radiation on human health are beneficial at or near current levels. We and others have shown that strict sun protection causes vitamin D-deficiency/insufficiency and that detection and treatment of vitamin D-deficiency in sun deprived risk groups is of high importance. Although further work is necessary to define an adequate vitamin D-status and adequate guidelines for solar and artificial UV-exposure, it is at present mandatory that public health campaigns and sun protection recommendations to prevent skin cancer consider these facts. In this review, we analyze the present literature to help developing well-balanced recommendations on sun protection that ensure an adequate vitamin D-status. These recommendations will hopefully protect us against adverse effects of UV protection without significantly increasing the risk to develop UV-induced skin cancer. PMID:20808512

A new biocompatible nanocomposite as a promising constituent of sunscreens.

PubMed

Amin, Rehab M; Elfeky, Souad A; Verwanger, Thomas; Krammer, Barbara

2016-06-01

Skin naturally uses antioxidants to protect itself from the damaging effects of sunlight. If this is not sufficient, other measures have to be taken. Like this, hydroxyapatite has the potential to be applied as an active constituent of sunscreens since calcium phosphate absorbs in the ultraviolet region (UV). The objective of the present work was to synthesize a hydroxyapatite-ascorbic acid nanocomposite (HAp/AA-NC) as a new biocompatible constituent of sunscreens and to test its efficiency with skin cell models. The synthesized HAp/AA-NC was characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, absorption spectrophotometry and X-ray diffraction analysis. The protective effect of the construct was tested with respect to viability and intracellular reactive oxygen species (ROS) generation of primary human dermal fibroblasts (SKIN) and human epidermal keratinocytes (HaCaT). Both cell lines were irradiated with UV light, λmax=254 nm with a fluence of 25 mJ cm(-2) to mimic the effect of UV radiation of sunlight on the skin. Results showed that HAp/AA-NC had a stimulating effect on the cell viability of both, HaCaT and SKIN cells, relative to the irradiated control. Intracellular ROS significantly decreased in UV irradiated cells when treated with HAp/AA-NC. We conclude that the synthesized HAp/AA-NC have been validated in vitro as a skin protector against the harmful effect of UV-induced ROS. Copyright © 2016 Elsevier B.V. All rights reserved.

Fluorescence image excited by a scanning UV-LED light

NASA Astrophysics Data System (ADS)

Tsai, Hsin-Yi; Chen, Yi-Ju; Huang, Kuo-Cheng

2013-03-01

An optical scanning system using UV-LED light to induced fluorescence technology can enhance a fluorescence image significantly in a short period. It has several advantages such as lower power consumption, no scattering effect in skins, and multilayer images can be obtained to analyze skin disease. From the experiment results, the light intensity increases with increase spot size and decrease scanning speed, but the image resolution is oppositely. Moreover, the system could be widely used in clinical diagnosis and photodynamic therapy for skin disease because even the irradiated time of fluorescence substance is short but it will provide accurately positioning of fluorescence object.

Differential co-promoting activities of alpha, beta and gamma interferons in the murine skin two-stage carcinogenesis model.

PubMed

Reiners, J J; Cantu, A; Thai, G; Pavone, A

1993-03-01

SENCAR mice develop more papillomas in two-stage skin carcinogenesis protocols if gamma interferon (IFN-gamma) is co-administered with 12-O-tetradecanoylphorbol-13-acetate (TPA) during the promotion phase. In the current study preparations of murine alpha, beta and gamma IFNs were surveyed for their abilities to modulate TPA-dependent promotion and induction of epidermal hyperplasia, inflammation and ornithine decarboxylase activity (ODC). Single or multiple i.p. administrations of IFN-alpha, -beta or -gamma (< or = 2500 units) did not induce epidermal hyperplasia, inflammation or ODC activity. Single or multiple i.p. administrations of IFN-alpha, -beta or -gamma (2500 units) to mice being topically promoted with 0.1 or 1 microgram of TPA did not alter the epidermal hyperplasia induced by the phorbol ester. The vascular permeability of the skin, as evaluated by the extravasation of Evans blue dye, was increased in a dose-dependent fashion by TPA over the range of 0.1-1 microgram. Treatment of mice promoted with 0.1 microgram of TPA with IFN-gamma (> or = 2500 units) significantly increased the skin's vascular permeability. Comparable effects were not obtained with IFN-beta (IFN-alpha not tested). Treatment of TPA-promoted mice with IFN-gamma, and to a lesser extent IFN-beta, weakly potentiated the TPA-dependent induction of epidermal ODC activity. Under conditions in which IFN-gamma had co-promoting activities in an initiation-promotion protocol, co-treatment of initiated mice with 1 microgram of TPA and IFN-alpha or -beta (100-5000 units) did not reproducibly alter tumor latency., or papilloma and carcinoma multiplicities. These findings suggest that the co-promoting activities of IFNs are restricted to the gamma class, and are not uniformly reflected by parameters commonly employed as short-term markers of tumor promotion.

UV-induced Melanin Chemiexcitation: A New Mode of Melanoma Pathogenesis.

PubMed

Brash, Douglas E

2016-06-01

Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts usually created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. Surprisingly, we found that, in melanocytes, CPDs were generated for hours after UVA or UVB exposure. These "dark CPDs" constituted the majority of CPDs in cultured human and murine melanocytes and in mouse skin, and they were most prominent in skin containing pheomelanin, the melanin responsible for blonde and red hair. The mechanism was also a surprise. Dark cyclobutane pyrimidine dimers (CPDs) arise when ultraviolet (UV)-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. This process, termed "chemiexcitation," is the source of bioluminescence in lower organisms. Excitation occurred in fragments of melanin, creating a quantum triplet state that had the energy of a UV photon but which induced CPDs by radiationless energy transfer to DNA. UVA and peroxynitrite also solubilized melanin and permeabilized the nuclear membrane, allowing melanin to enter. Melanin is evidently carcinogenic as well as protective. Chemiexcitation may also trigger pathogenesis in internal tissues because the same chemistry should arise wherever superoxide and nitric oxide arise near cells that contain melanin. © The Author(s) 2016.

Chemopreventive effects of the juice of Vitis coignetiae Pulliat on two-stage mouse skin carcinogenesis.

PubMed

Arimoto-Kobayashi, Sakae; Zhang, Xiaomeng; Yuhara, Yuta; Kamiya, Tomonori; Negishi, Tomoe; Okamoto, Goro

2013-01-01

Our study revealed the inhibitory effect of Vitis coignetiae Pulliat, known as Yamabudo in Japan, at the stages of multi-step carcinogenesis. The juice of Vitis coignetiae (Y-grape juice) was antimutagenic toward dimethylbenzo[a]anthracene (DMBA), aflatoxin B1, and benzo[a]pyrene in the Ames test. The Y-grape juice was also antigenotoxic in the micronucleus test using HepG2 cells toward DMBA and aflatoxin B1. Topical and oral administration of the Y-grape juice to mice inhibited the induction of inflammation of 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical and oral administration of the Y-grape juice significantly decreased the incidence and mean number of tumors in mice skin with the 2-stage tumorigenesis protocol. To elucidate the mechanisms underlying the antiinflammatory and antitumor promotion activity of the Y-grape juice, the effect of Y-grape juice on cyclooxygenase-2 (COX-2) activity in mouse ear treated with TPA was studied. Both topical and oral application of the Y-grape juice inhibited the TPA-induced increase in COX-2 activity. Caftaric acid, isolated and identified from the Y-grape juice, was antimutagenic toward DMBA and prevented TPA-induced inflammation in mice, suggesting caftaric acid participates in chemopreventive effect/activities of Y-grape juice.

[Epidemiology of occupational skin cancer due to UV-irradiation].

PubMed

Diepgen, T L; Drexler, H; Schmitt, J

2012-10-01

Skin cancer induced by occupational UV-irradiation is not an official occupational disease number in the appendix of the German ordinance on occupational diseases (Berufskrankheitenverordnung (BKV) but can be recognized as a "virtually" occupational disease according to § 9 (2) of the 7th book of the German Social Code (SGB VII). Epidemiological studies have demonstrated a positive, statistically significant and relevant association between occupational UV-irradiation and the risk of squamous cell carcinoma (SCC) and actinic keratoses (AK). Outdoor workers have on average a 100% higher risk to develop SCC compared to the general population. Therefore, the prerequisites for a new occupational disease are fulfilled and SCC and AK should be reported as an occupational disease if an additional 40% occupationally-related UV-irradiation is documented and the clinical criteria are typical for work- related skin cancer. Epidemiologic evidence also indicates a significant association between work-related UV-irradiation and basal cell carcinoma (BCC) risk: however the results are less consistent and the association is weaker than with SCC. There is an urgent need for further studies in outdoor workers on BCC and lentigo maligna melanoma.

Protective effects of the antioxidant extract collected from Styela clava tunics on UV radiation‑induced skin aging in hairless mice.

PubMed

Koh, Eun Kyoung; Kim, Ji Eun; Go, Jun; Song, Sung Hwa; Sung, Ji Eun; Son, Hong Joo; Jung, Young Jin; Kim, Bae Hwan; Jung, Young Suk; Hwang, Dae Youn

2016-11-01

Ultraviolet (UV) radiation is considered a primary cause of skin damage, which is characterized by deep wrinkles, roughness, laxity and pigmentation through oxidative stress and oxidative photodamage. To examine the therapeutic effects of ethanol extract of Styela clava tunics (EtSCT) on UV radiation-induced skin aging in hairless mice, alterations in skin phenotype, histological structures, inflammation, endoplasmic reticulum (ER) stress, oxidative conditions and toxicity were investigated during 13 weeks of UV irradiation and topical application of EtSCT. EtSCT showed high reducing power (3.1%), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (92.7%) and NO scavenging activity (15.6%) due to its high total flavonoids (15.3 mg/ml) and total phenolics (36.8 mg/ml). The topical application of EtSCT suppressed photoaging of the skin of UV-irradiated mice, and this was demonstrated by the inhibition of wrinkle formation, the suppression of the erythema index as well as the prevention of transepidermal water loss. Additionally, the epidermal thickness and adipocytes number were recovered to a similar level as that in the no radiation group in the UV + EtSCT‑treated groups compared with the UV + vehicle‑treated group, and the expression of collagen I increased. The attenuation of mitogen‑activated protein kinase and ER stress signaling pathways activated by reactive oxygen species was also detected in the UV + EtSCT‑treated group. Inflammatory responses including the infiltration of mast cells, CD31 expression and interleukin-6 secretion were significantly lower in the UV + EtSCT-treated groups. Moreover, the concentration of malondialdehyde was reduced and the activity of superoxide dismutase was effectively recovered in the UV + EtSCT-treated groups compared with that in the vehicle-treated groups. Liver and kidney toxicity factors were maintained at a constant level. These results suggest that EtSCT has the potential for use as therapeutic drug which protects against skin aging by regulating the skin morphology, histopathological structures, ER stress, inflammation and oxidative conditions.

Skin cancer in skin of color: an update on current facts, trends, and misconceptions.

PubMed

Battie, Claire; Gohara, Mona; Verschoore, Michèle; Roberts, Wendy

2013-02-01

For many fair-skinned individuals around the world, skin cancer is the leading malignancy. Although skin cancer comprises only 1% to 2% of all malignancies in those with darker complexions, the mortality rates in this subgroup are substantially higher when compared with their Caucasian counterparts. This discrepancy is largely as a result of delayed detection/treatment, and a false perception among patient and physician that brown skin confers complete protection against skin cancer. Recent studies show that 65% of surveyed African Americans never wore sunscreen, despite living in sunny climates, and that more than 60% of minority respondents erroneously believed that they were not at risk for skin cancer. Dark skin offers some protection from ultraviolet (UV) light. However, there is considerable heterogeneity in skin of color, a phenomenon that is accentuated by mixed heritage. Ethnicity does not confer skin type anymore. People of color do experience sunburn, and from a biological point of view, all skin types appear to be sensitive to UV-induced DNA damage, with an inverse relationship between skin color and sensitivity to UV light. Our population is changing rapidly, and within the next few decades minority populations will become the majority. It is therefore imperative to educate both physicians and patients on the perceived immunity against cutaneous malignancies, the need for sun protection, and the clinical signs of skin cancer in non-Caucasian people, so that future unnecessary mortality can be avoided.

Myricetin inhibits UVB-induced angiogenesis by regulating PI-3 kinase in vivo

PubMed Central

Jung, Sung Keun; Lee, Ki Won; Byun, Sanguine; Lee, Eun Jung; Kim, Jong-Eun; Bode, Ann M.; Dong, Zigang

2010-01-01

Myricetin is one of the principal phytochemicals in onions, berries and red wine. Previous studies showed that myricetin exhibits potent anticancer and chemopreventive effects. The present study examined the effect of myricetin on ultraviolet (UV) B-induced angiogenesis in an SKH-1 hairless mouse skin tumorigenesis model. Topical treatment with myricetin inhibited repetitive UVB-induced neovascularization in SKH-1 hairless mouse skin. The induction of vascular endothelial growth factor, matrix metalloproteinase (MMP)-9 and MMP-13 expression by chronic UVB irradiation was significantly suppressed by myricetin treatment. Immunohistochemical and western blot analyses revealed that myricetin inhibited UVB-induced hypoxia inducible factor-1α expression in mouse skin. Western blot analysis and kinase assay data revealed that myricetin suppressed UVB-induced phosphatidylinositol-3 (PI-3) kinase activity and subsequently attenuated the UVB-induced phosphorylation of Akt/p70S6K in mouse skin lysates. A pull-down assay revealed the direct binding of PI-3 kinase and myricetin in mouse skin lysates. Our results indicate that myricetin suppresses UVB-induced angiogenesis by regulating PI-3 kinase activity in vivo in mouse skin. PMID:20008033

Protective effects of citrus and rosemary extracts on UV-induced damage in skin cell model and human volunteers.

PubMed

Pérez-Sánchez, A; Barrajón-Catalán, E; Caturla, N; Castillo, J; Benavente-García, O; Alcaraz, M; Micol, V

2014-07-05

Ultraviolet radiation absorbed by the epidermis is the major cause of various cutaneous disorders, including photoaging and skin cancers. Although topical sunscreens may offer proper skin protection, dietary plant compounds may significantly contribute to lifelong protection of skin health, especially when unconsciously sun UV exposed. A combination of rosemary and citrus bioflavonoids extracts was used to inhibit UV harmful effects on human HaCaT keratinocytes and in human volunteers after oral intake. Survival of HaCaT cells after UVB radiation was higher in treatments using the combination of extracts than in those performed with individual extracts, indicating potential synergic effects. The combination of extracts also decreased UVB-induced intracellular radical oxygen species (ROS) and prevented DNA damage in HaCaT cells by comet assay and decreased chromosomal aberrations in X-irradiated human lymphocytes. The oral daily consumption of 250 mg of the combination by human volunteers revealed a significant minimal erythema dose (MED) increase after eight weeks (34%, p<0.05). Stronger protection was achieved after 12 weeks (56%, p<0.01). The combination of citrus flavonoids and rosemary polyphenols and diterpenes may be considered as an ingredient for oral photoprotection. Their mechanism of action may deserve further attention. Copyright © 2014 Elsevier B.V. All rights reserved.

Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches.

PubMed

Lehmann, Janin; Schubert, Steffen; Emmert, Steffen

2014-10-01

Xeroderma pigmentosum (XP) is an autosomal recessive disease, caused by a gene defect in the nucleotide-excision-repair (NER) pathway or in translesional DNA synthesis. At the age of eight, patients already develop their first skin cancers due to this DNA repair defect. In contrast, in the Caucasian population the first tumor formation in UV exposed skin regions occurs at a mean age of 60. The clinical picture among patients suffering from XP is highly diverse and includes signs of accelerated skin aging, and UV-induced skin cancers, as well as ophthalmologic and neurological symptoms. Patients should therefore receive interdisciplinary care. This includes dermatologists, ophthalmologists, ENT specialists, neurologists, and human geneticists. Patients with XP are clinically diagnosed, but this may be supported by molecular-genetic and functional analyses. These analyses allow pinpointing the exact disease-causing gene defect (complementation group assignment, detection of the type and location of the mutation within the gene). The resulting information is already relevant to predict the course of disease and symptoms and probably will be utilized for individualized therapeutic approaches in the future. Recently, enhanced repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons by certain antibiotics could be demonstrated. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

PubMed Central

Breuckmann, Frank; Gambichler, Thilo; Altmeyer, Peter; Kreuter, Alexander

2004-01-01

Background Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. Methods Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. Results Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. Conclusions Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications. PMID:15380024

A molecular systems approach to modelling human skin pigmentation: identifying underlying pathways and critical components.

PubMed

Raghunath, Arathi; Sambarey, Awanti; Sharma, Neha; Mahadevan, Usha; Chandra, Nagasuma

2015-04-29

Ultraviolet radiations (UV) serve as an environmental stress for human skin, and result in melanogenesis, with the pigment melanin having protective effects against UV induced damage. This involves a dynamic and complex regulation of various biological processes that results in the expression of melanin in the outer most layers of the epidermis, where it can exert its protective effect. A comprehensive understanding of the underlying cross talk among different signalling molecules and cell types is only possible through a systems perspective. Increasing incidences of both melanoma and non-melanoma skin cancers necessitate the need to better comprehend UV mediated effects on skin pigmentation at a systems level, so as to ultimately evolve knowledge-based strategies for efficient protection and prevention of skin diseases. A network model for UV-mediated skin pigmentation in the epidermis was constructed and subjected to shortest path analysis. Virtual knock-outs were carried out to identify essential signalling components. We describe a network model for UV-mediated skin pigmentation in the epidermis. The model consists of 265 components (nodes) and 429 directed interactions among them, capturing the manner in which one component influences the other and channels information. Through shortest path analysis, we identify novel signalling pathways relevant to pigmentation. Virtual knock-outs or perturbations of specific nodes in the network have led to the identification of alternate modes of signalling as well as enabled determining essential nodes in the process. The model presented provides a comprehensive picture of UV mediated signalling manifesting in human skin pigmentation. A systems perspective helps provide a holistic purview of interconnections and complexity in the processes leading to pigmentation. The model described here is extensive yet amenable to expansion as new data is gathered. Through this study, we provide a list of important proteins essential for pigmentation which can be further explored to better understand normal pigmentation as well as its pathologies including vitiligo and melanoma, and enable therapeutic intervention.

Quercitrin Protects Skin from UVB-induced Oxidative Damage

PubMed Central

Yin, Yuanqin; Li, Wenqi; Son, Yong-Ok; Sun, Lijuan; Lu, Jian; Kim, Donghern; Wang, Xin; Yao, Hua; Wang, Lei; Pratheeshkumar, Poyil; Hitron, Andrew J; Luo, Jia; Gao, Ning; Shi, Xianglin; Zhang, Zhuo

2013-01-01

Exposure of the skin to ultraviolet B (UVB) radiation causes oxidative damage to skin, resulting in sunburn, photoaging, and skin cancer. It is generally believed that the skin damage induced by UV irradiation is a consequence of generation of reactive oxygen species (ROS). Recently, there is an increased interest in the use of natural products as chemopreventive agents for non-melanoma skin cancer (NMSC) due to their antioxidants and anti-inflammatory properties. Quercitrin, glycosylated form of quercetin, is the most common flavonoid in nature with antioxidant properties. The present study investigated the possible beneficial effects of quercitrin to inhibit UVB irradiation-induced oxidative damage in vitro and in vivo. Our results showed that quercitrin decreased ROS generation induced by UVB irradiation in JB6 cells. Quercitrin restored catalase expression and GSH/GSSG ratio reduced by UVB exposure, two major antioxidant enzymes, leading to reductions of oxidative DNA damage and apoptosis and protection of the skin from inflammation caused by UVB exposure. The present study demonstrated that quercitrin functions as an antioxidant against UVB irradiation-induced oxidative damage to skin. PMID:23545178

Quercitrin protects skin from UVB-induced oxidative damage.

PubMed

Yin, Yuanqin; Li, Wenqi; Son, Young-Ok; Sun, Lijuan; Lu, Jian; Kim, Donghern; Wang, Xin; Yao, Hua; Wang, Lei; Pratheeshkumar, Poyil; Hitron, Andrew J; Luo, Jia; Gao, Ning; Shi, Xianglin; Zhang, Zhuo

2013-06-01

Exposure of the skin to ultraviolet B (UVB) radiation causes oxidative damage to skin, resulting in sunburn, photoaging, and skin cancer. It is generally believed that the skin damage induced by UV irradiation is a consequence of generation of reactive oxygen species (ROS). Recently, there is an increased interest in the use of natural products as chemopreventive agents for non-melanoma skin cancer (NMSC) due to their antioxidants and anti-inflammatory properties. Quercitrin, glycosylated form of quercetin, is the most common flavonoid in nature with antioxidant properties. The present study investigated the possible beneficial effects of quercitrin to inhibit UVB irradiation-induced oxidative damage in vitro and in vivo. Our results showed that quercitrin decreased ROS generation induced by UVB irradiation in JB6 cells. Quercitrin restored catalase expression and GSH/GSSG ratio reduced by UVB exposure, two major antioxidant enzymes, leading to reductions of oxidative DNA damage and apoptosis and protection of the skin from inflammation caused by UVB exposure. The present study demonstrated that quercitrin functions as an antioxidant against UVB irradiation-induced oxidative damage to skin. Copyright © 2013 Elsevier Inc. All rights reserved.

Skin and antioxidants.

PubMed

Poljsak, Borut; Dahmane, Raja; Godic, Aleksandar

2013-04-01

It is estimated that total sun exposure occurs non-intentionally in three quarters of our lifetimes. Our skin is exposed to majority of UV radiation during outdoor activities, e.g. walking, practicing sports, running, hiking, etc. and not when we are intentionally exposed to the sun on the beach. We rarely use sunscreens during those activities, or at least not as much and as regular as we should and are commonly prone to acute and chronic sun damage of the skin. The only protection of our skin is endogenous (synthesis of melanin and enzymatic antioxidants) and exogenous (antioxidants, which we consume from the food, like vitamins A, C, E, etc.). UV-induced photoaging of the skin becomes clinically evident with age, when endogenous antioxidative mechanisms and repair processes are not effective any more and actinic damage to the skin prevails. At this point it would be reasonable to ingest additional antioxidants and/or to apply them on the skin in topical preparations. We review endogenous and exogenous skin protection with antioxidants.

[The role of free radicals in the UV-induced skin damage. Photo-aging].

PubMed

Emri, Gabriella; Horkay, Irén; Remenyik, Eva

2006-04-23

The natural (intrinsic) ageing of the skin is enhanced by environmental factors (extrinsic ageing). One of the most important exogenous factors is the solar UV exposure, which results in photo-aging. Besides this, epidemiological and experimental data show a rapid increase in the incidence of human skin cancers, which is also in relation to the increased sunlight exposure of the skin. In the background of these processes there are cell biological effects, photochemical reactions, membrane receptor changes, lipid- and protein modifications, DNA-damage induced by UV. The qualities and quantities of them are wavelength dependent. The UVB photons are absorbed mostly by the DNA of the epidermal keratinocytes, therefore this spectrum is more relevant for photocarcinogenesis. The effect of UVA-irradiation is mainly manifested in the induction of free radicals, which have not only DNA-damaging, but also immunomodulating effect, which also can influence on tumour development. Furthermore, the free radicals cause dermal connective tissue damage as well via activating transcription factors, inducing matrix metalloproteinases, diminishing the procollagen I and fibrillin-1 synthesis. These processes are augmented by mitochondrial DNA mutations, protein oxidation, apoptosis induction. Therefore the enzymes neutralising free radicals and antioxidant molecules, respectively, have an important role in the defence mechanisms. In the therapy of photo-aging the local retinoids lived up to expectations, but the clinical effectiveness of antioxidant vitamins is lower than expected. The most important factor in the prevention of the photo-aging and photocarcinogenesis is the sun protection at present.

Skin protection against UV light by dietary antioxidants.

PubMed

Fernández-García, Elisabet

2014-09-01

There is considerable interest in the concept of additional endogenous photoprotection by dietary antioxidants. A number of efficient micronutrients are capable of contributing to the prevention of UV damage in humans. These compounds protect molecular targets by scavenging reactive oxygen species, including excited singlet oxygen and triplet state molecules, and also modulate stress-dependent signaling and/or suppress cellular and tissue responses like inflammation. Micronutrients present in the diet such as carotenoids, vitamins E and C, and polyphenols contribute to antioxidant defense and may also contribute to endogenous photoprotection. This review summarizes the literature concerning the use of dietary antioxidants as systemic photoprotective agents towards skin damage induced by UVA and UVB. Intervention studies in humans with carotenoid-rich diets have shown photoprotection. Interestingly, rather long treatment periods (a minimum of 10 weeks) were required to achieve this effect. Likewise, dietary carotenoids exert their protective antioxidant function in several in vitro and in vivo studies when present at sufficiently high concentration. A combination of vitamins E and C protects the skin against UV damage. It is suggested that daily consumption of dietary polyphenols may provide efficient protection against the harmful effects of solar UV radiation in humans. Furthermore, the use of these micronutrients in combination may provide an effective strategy for protecting human skin from damage by UV exposure.

Epigenetic regulation of MdMYB1 is associated with paper bagging-induced red pigmentation of apples.

PubMed

Bai, Songling; Tuan, Pham Anh; Saito, Takanori; Honda, Chikako; Hatsuyama, Yoshimichi; Ito, Akiko; Moriguchi, Takaya

2016-09-01

Paper-bagging treatment can transform non-transcribed MdMYB1 - 2 and MdMYB1 - 3 alleles into transcribed alleles through epigenetic regulations, resulting in the red pigmentation of a normally non-red apple cultivar 'Mutsu.' Anthocyanin biosynthesis in apples is regulated by MdMYB1/A/10, an R2R3-Type MYB gene. 'Mutsu,' a triploid apple cultivar harboring non-transcribed MdMYB1-2 and MdMYB1-3 alleles, retains green skin color under field conditions. However, it can show red/pink pigmentation under natural or artificial ultraviolet-B (UV-B) light exposure after paper-bagging and bag removal treatment. In the present study, we found that in 'Mutsu,' paper bagging-induced red pigmentation was due to the activation of non-transcribed MdMYB1-2/-3 alleles, which triggered the expression of downstream anthocyanin biosynthesis genes in a UV-B-dependent manner. By monitoring the epigenetic changes during UV-B-induced pigmentation, no significant differences in DNA methylation and histone modifications in the 5' upstream region of MdMYB1-2/-3 were recorded between the UV-B-treated fruit skin (red) and the fruit skin treated only by white light (green). In contrast, bag treatment lowered the DNA methylation in this region of MdMYB1-2/-3 alleles. Similarly, higher levels of histone H3 acetylation and trimethylation of H3 tail at lysine 4, and lower level of trimethylation of H3 tail at lysine 27 were observed in the 5' upstream region of MdMYB1-2/-3 in the skin of the fruit immediately after bag removal. These results suggest that bagging treatment can induce epigenetic changes, facilitating the binding of trans factor(s) to MdMYB1-2/-3 alleles, resulting in the activation of these MYBs after bag removal.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Siddens, Lisbeth K.; Superfund Research Center, Oregon State University, Corvallis, OR 97331; Bunde, Kristi L.

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,more » 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.« less

In Vivo Suppression of Heat Shock Protein (HSP)27 and HSP70 Accelerates DMBA-Induced Skin Carcinogenesis by Inducing Antigenic Unresponsiveness to the Initiating Carcinogenic Chemical.

PubMed

Yusuf, Nabiha; Nasti, Tahseen H; Ahmad, Israr; Chowdhury, Sanim; Mohiuddin, Hasan; Xu, Hui; Athar, Mohammad; Timares, Laura; Elmets, Craig A

2015-05-15

Heat shock proteins (HSPs) are constitutively expressed in murine skin. HSP27 is present in the epidermis, and HSP70 can be found in both the epidermis and dermis. The purpose of this study was to investigate the role of these proteins in cutaneous chemical carcinogenesis and to determine whether their effects on cell-mediated immune function were a contributing factor. In vivo inhibition of HSP27 and HSP70 produced a reduction in the T cell-mediated immune response to 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene in C3H/HeN mice and resulted in a state of Ag-specific tolerance. When mice were pretreated with anti-HSP27 and anti-HSP70 Abs in vivo prior to subjecting them to a standard two-stage DMBA/12-O-tetradecanoylphorbol-13-acetate cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (p < 0.05) in anti-HSP27- and HSP70-pretreated animals compared with mice pretreated with control Ab. Similar results were obtained when the data were evaluated as the cumulative number of tumors per group. Mice pretreated with HSP27 and HSP70 Abs developed more H-ras mutations and fewer DMBA-specific cytotoxic T lymphocytes. These findings indicate that in mice HSP27 and HSP70 play a key role in the induction of cell-mediated immunity to carcinogenic polyaromatic hydrocarbons. Bolstering the immune response to carcinogenic polyaromatic hydrocarbons may be an effective method for prevention of the tumors that they produce. Copyright © 2015 by The American Association of Immunologists, Inc.

High-fat diet exacerbates inflammation and cell survival signals in the skin of ultraviolet B-irradiated C57BL/6 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meeran, Syed M.; Singh, Tripti; Nagy, Tim R.

Inflammation induced by chronic exposure to ultraviolet (UV) radiation has been implicated in various skin diseases. We formulated the hypothesis that a high-fat diet may influence the UV-induced inflammatory responses in the skin. C57BL/6 mice were fed a high-fat diet or control diet and exposed to UVB radiation (120 mJ/cm{sup 2}) three times/week for 10 weeks. The mice were then sacrificed and skin and plasma samples collected for analysis of biomarkers of inflammatory responses using immunohistochemistry, western blotting, ELISA and real-time PCR. We found that the levels of inflammatory biomarkers were increased in the UVB-exposed skin of the mice fedmore » the high-fat diet than the UVB-exposed skin of the mice fed the control diet. The levels of inflammatory biomarkers of early responses to UVB exposure (e.g., myeloperoxidase, cyclooxygenase-2, prostaglandin-E{sub 2}), proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), and proliferating cell nuclear antigen and cell survival signals (phosphatidylinositol-3-kinase and p-Akt-Ser{sup 473}) were higher in high-fat-diet-fed mouse skin than control-diet-fed mouse skin. The plasma levels of insulin growth factor-1 were greater in the UVB-irradiated mice fed the high-fat diet than the UVB-irradiated mice fed the control diet, whereas the levels of plasma adiponectin were significantly lower. This pronounced exacerbation of the UVB-induced inflammatory responses in the skin of mice fed a high-fat diet suggests that high-fat diet may increase susceptibility to inflammation-associated skin diseases, including the risk of skin cancer.« less

Effect of topical sunscreens on the UV-radiation-induced suppression of the alloactivating capacity in human skin in vivo.

PubMed

van Praag, M C; Out-Luyting, C; Claas, F H; Vermeer, B J; Mommaas, A M

1991-10-01

Exposure of mice or humans to solar or artificial ultraviolet radiation (UV) has been shown to induce a number of changes in the immune system that may influence their susceptibility to skin tumors. The protective effect of sunscreens on these changes is not clear. Thirty-two patients with a variety of dermatoses routinely undergoing treatment with standard UVB (n = 19) or PUVA (n = 13) therapy were studied. One of the two tested sunscreens or its vehicle was applied to the right flexor forearm immediately prior to each total-body UV exposure. Epidermal sheets were obtained by the suction-blister method from the left flexor forearm before treatment and from both flexor forearms after 4 weeks of photo- or photochemotherapy and used as stimulator epidermal cells (EC) in the mixed epidermal cell-lymphocyte reaction (MECLR). After 4 weeks of either UVB or PUVA therapy the MECLR responses on EC from both arms were markedly decreased. Neither the tested sunscreens nor their vehicles prevented the UV-induced suppression of the alloactivating capacity. The failure of sunscreens to protect against the UV-induced suppression of the alloactivating capacity could be explained in two ways. First, the energy not absorbed by the sunscreen could be sufficient to induce suppression of the alloactivating capacity. An alternative explanation could be systemic immune suppression by UV. In order to discriminate between these possibilities only the right forearms of 10 healthy volunteers, treated with a sunscreen or its vehicle, were irradiated with UVB during 4 weeks. In this manner systemic immune suppression by UVB could be excluded. This experiment resulted in a similar suppression of the MECLR responses, as induced by total body UVB irradiation, without any protection by the sunscreen. Apparently, the UV dose not absorbed by the sunscreen was capable to induce suppression of the alloactivating capacity. Our results indicate that people protected from sunburn by sunscreens may be exposed to UV for a long period of time, and thereby subject themselves to its immunosuppressive action.

N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of UV-induced melanoma in mice

PubMed Central

Cotter, Murray A.; Thomas, Joshua; Cassidy, Pamela; Robinette, Kyle; Jenkins, Noah; Scott, R. Florell; Leachman, Sancy; Samlowski, Wolfram E.; Grossman, Douglas

2008-01-01

UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. In melan-a cells, a mouse melanocyte line, NAC (1–10 mM) conferred protection from several UV-induced oxidative sequelae including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine (8-OG), and depletion of free reduced thiols (primarily glutathione). Mice transgenic for hepatocyte growth factor and Survivin, previously shown to develop melanoma following a single neonatal dose of UV irradiation, were administered NAC (7 mg/ml, mother’s drinking water) transplacentally and through nursing until two weeks after birth. Delivery of NAC in this manner reduced thiol depletion and blocked formation of 8-OG in skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared to control mice (21 vs. 14 weeks, p=0.0003). Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma, and suggest that NAC may be useful as a chemopreventive agent. PMID:17908992

Broad-spectrum sunscreens offer protection against urocanic acid photoisomerization by artificial ultraviolet radiation in human skin.

PubMed

van der Molen, R G; Out-Luiting, C; Driller, H; Claas, F H; Koerten, H K; Mommaas, A M

2000-09-01

Cis-urocanic acid (UCA) has been indicated as an important mediator of ultraviolet (UV)-induced immunosuppression. In this study we describe a rapid, noninvasive method for the determination of the protective capacity of various sunscreens against the UV-induced isomerization of trans-UCA into its cis form. For this purpose we applied sunscreens prior to in vivo exposure of human volunteers with single or repeated broadband UVB irradiations of 100 mJ per cm2. We found significant but different levels of protection against UCA photoisomerization by all sunscreens that correlated with the sun protection factor. A comparison of various sunscreens with a sun protection factor of 10, showed that the best protection was offered by the sunscreens (containing organic UV filters or TiO2) with broad absorption spectra. The ability to inhibit cis-UCA formation was not influenced by the penetration characteristics of sunscreens, as determined by application of the sunscreen on quartz glass that was placed on the skin, preventing penetration of sunscreen in the skin. In addition ex vivo UV exposure of human skin was employed to permit other tests of immunomodulation, in this case the mixed epidermal cell lymphocyte reaction. The advantage of this ex vivo method is that there is no need to take biopsies from volunteers. Ex vivo irradiation of human skin with a single dose of 200 mJ per cm2 resulted in similar protection by the sunscreens against cis-UCA formation as in the in vivo system. Furthermore, the mixed epidermal cell lymphocyte reaction data correlated with the cis-UCA findings. We conclude that UCA isomerization is an excellent method to determine sunscreen efficacy and that broad-spectrum sunscreens offer good immunoprotection.

Visible Light Induces Melanogenesis in Human Skin through a Photoadaptive Response

PubMed Central

Randhawa, Manpreet; Seo, InSeok; Liebel, Frank; Southall, Michael D.; Kollias, Nikiforos; Ruvolo, Eduardo

2015-01-01

Visible light (400–700 nm) lies outside of the spectral range of what photobiologists define as deleterious radiation and as a result few studies have studied the effects of visible light range of wavelengths on skin. This oversight is important considering that during outdoors activities skin is exposed to the full solar spectrum, including visible light, and to multiple exposures at different times and doses. Although the contribution of the UV component of sunlight to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology in terms of inflammation, and limited information is available regarding the role of visible light on pigmentation. The purpose of this study was to determine the effect of visible light on the pro-pigmentation pathways and melanin formation in skin. Exposure to visible light in ex-vivo and clinical studies demonstrated an induction of pigmentation in skin by visible light. Results showed that a single exposure to visible light induced very little pigmentation whereas multiple exposures with visible light resulted in darker and sustained pigmentation. These findings have potential implications on the management of photo-aggravated pigmentary disorders, the proper use of sunscreens, and the treatment of depigmented lesions. PMID:26121474

Caffeine decreases phospho-Chk1 (Ser317) and increases mitotic cells with cyclin B1 and caspase 3 in tumors from UVB-treated mice.

PubMed

Lu, Yao-Ping; Lou, You-Rong; Peng, Qing-Yun; Nghiem, Paul; Conney, Allan H

2011-07-01

Oral administration of caffeine to mice inhibits UVB-induced carcinogenesis, and these results are paralleled by epidemiology studies indicating that caffeinated coffee and tea intake (but not decaffeinated beverage intake) is associated with decreased incidence of nonmelanoma skin cancer. Topical applications of caffeine to the skin of SKH-1 mice that had previously been treated with UVB inhibited subsequent skin tumor development and stimulated apoptosis in tumors but not in nontumor areas of the epidermis. This study sought to determine the basis of these differential effects on tumor versus nontumor sites that can be induced by caffeine, long after all UVB treatment has ceased. The activation status of the ATR/Chk1 pathway in UVB-induced tumors and uninvolved skin was determined by quantitating phospho-Chk1 (Ser317) and induction of lethal mitosis in vivo in the presence and absence of topical caffeine treatment. In the absence of caffeine, we found that UVB-induced tumors often had islands of phospho-Chk1 (Ser317) staining cells that were not present in nontumor areas of the epidermis. Treatment of mice with topical caffeine significantly diminished phospho-Chk1 (Ser317) staining and increased the number of mitotic cells that expressed cyclin B1 and caspase 3 in tumors, consistent with caffeine-induced lethal mitosis selectively in tumors. We hypothesize that compared with adjacent uninvolved skin, UVB-induced skin tumors have elevated activation of, and dependence on, the ATR/Chk1 pathway long after UVB exposure has ceased and that caffeine can induce apoptosis selectively in tumors by inhibiting this pathway and promoting lethal mitosis.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vaid, Mudit; Singh, Tripti; Prasad, Ram

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 ofmore » 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 consumption of low-fat diet may inhibit the risk of photocarcinogenesis.« less

Skin protective effect of guava leaves against UV-induced melanogenesis via inhibition of ORAI1 channel and tyrosinase activity.

PubMed

Lee, Dong-Ung; Weon, Kwon Yeon; Nam, Da-Yeong; Nam, Joo Hyun; Kim, Woo Kyung

2016-12-01

Ultraviolet (UV) irradiation is a major environmental factor affecting photoageing, which is characterized by skin wrinkle formation and hyperpigmentation. Although many factors are involved in the photoageing process, UV irradiation is thought to play a major role in melanogenesis. Tyrosinase is the key enzyme in melanin synthesis; therefore, many whitening agents target tyrosinase through various mechanisms, such as direct interference of tyrosinase catalytic activity or inhibition of tyrosinase mRNA expression. Furthermore, the highly selective calcium channel ORAI1 has been shown to be associated with UV-induced melanogenesis. Thus, ORAI1 antagonists may have applications in the prevention of melanogenesis. Here, we aimed to identify the antimelanogenesis agents from methanolic extract of guava leaves (Psidium guajava) that can inhibit tyrosinase and ORAI1 channel. The n-butanol (47.47%±7.503% inhibition at 10 μg/mL) and hexane (57.88%±7.09% inhibition at 10 μg/mL) fractions were found to inhibit ORAI1 channel activity. In addition, both fractions showed effective tyrosinase inhibitory activity (68.3%±0.50% and 56.9%±1.53% inhibition, respectively). We also confirmed that the hexane fraction decreased the melanin content induced by UVB irradiation and the ET-1-induced melanogenesis in murine B16F10 melanoma cells. These results suggest that the leaves of P. guajava can be used to protect against direct and indirect UV-induced melanogenesis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Aqueous Extract of Chrysanthemum morifolium (菊花 Jú Huā) Enhances the Antimelanogenic and Antioxidative Activities of the Mixture of Soy Peptide and Collagen Peptide

PubMed Central

Gui, Min; Du, Jun; Guo, Jianmin; Xiao, Baiquan; Yang, Wei; Li, Minjie

2014-01-01

The possible synergistic effect between the aqueous extract of Chrysanthemum morifolium (菊花 Jú Huā) (AECM) and the peptide mixture (PM) containing soy peptide and collagen peptide was investigated in an ultraviolet (UV) irradiation–induced skin damage mouse model. The irradiated mice were treated with the PM or PM + AECM (containing PM and AECM), respectively. Both PM and PM + AECM groups displayed an apparent photoprotective effect on the UV-irradiated skin damage of mice. Histological evaluation demonstrated that the epidermal hyperplasia and melanocytes in the basal epidermal layer of the UV-irradiated skin in mice decreased when treated with either PM or PM + AECM. Further study showed that soy peptide, collagen peptide, and AECM also inhibited the activities of mushroom tyrosinase with IC50 values of 82.3, 28.2, and 1.6 μg/ml, respectively. Additionally, PM + AECM reduced melanogenesis by 46.2% at the concentration of 10 mg/ml in B16 mouse melanoma cells. Meanwhile, the UV-induced increase of antioxidative indicators, including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyde (MDA), was reduced significantly after treatment with 1.83 g/kg/dbw of PM + AECM. This evidence supported the synergistic antioxidative effect of AECM with PM. These results demonstrated that oral intake of PM and AECM had synergistic antimelanogenic and antioxidative effects in UV-irradiated mice. PMID:25161922

Protective effect of maghemite nanoparticles on ultraviolet-induced photo-damage in human skin fibroblasts

NASA Astrophysics Data System (ADS)

Lee, Kwon-Jai; An, Jeung-Hee; Shin, Jae-Soo; Kim, Dong-Hee; Kim, Changman; Ozaki, Hajime; Koh, Jae-Gui

2007-11-01

This study examined the optical properties of an oxidized form of maghemite (γ-Fe2O3) nanoparticles and their protective effects against the photoaging of human skin fibroblasts irradiated with ultraviolet (UV) light. Nanoparticles with diameters ranging from 8.7 to 12 nm were prepared using a chemical co-precipitation method. The nanoparticles were coated with two surfactants to obtain a water-based product. The onset of the absorption of the γ-Fe2O3 nanoparticles in the UV-visible absorption spectra increased with increasing particle size. The γ-Fe2O3 nanoparticles significantly inhibited the production of matrix metalloproteinase-1 in human skin fibroblast HS 68 cells by 60% compared with the UV-irradiated control. These results suggest that γ-Fe2O3 nanoparticles have photoprotective properties, and have potential use as an agent against photoaging.

IL27 controls skin tumorigenesis via accumulation of ETAR-positive CD11b cells in the pre-malignant skin

PubMed Central

Dibra, Denada; Mitra, Abhisek; Newman, Melissa; Xia, Xueqing; Keenan, Camille; Cutrera, Jeffry J.; Mathis, J. Michael; Wang, Xiao-Jing; Myers, Jeffrey; Li, Shulin

2016-01-01

Establishment of a permissive pre-malignant niche in concert with mutant stem are key triggers to initiate skin carcinogenesis. An understudied area of research is finding upstream regulators of both these triggers. IL27, a pleiotropic cytokine with both pro- and anti-inflammatory properties, was found to be a key regulator of both. Two step skin carcinogenesis model and K15-KRASG12D mouse model were used to understand the role of IL27 in skin tumors. CD11b−/− mice and small-molecule of ETAR signaling (ZD4054) inhibitor were used in vivo to understand mechanistically how IL27 promotes skin carcinogenesis. Interestingly, using in vivo studies, IL27 promoted papilloma incidence primarily through IL27 signaling in bone-marrow derived cells. Mechanistically, IL27 initiated the establishment of the pre-malignant niche and expansion of mutated stem cells in K15-KRASG12D mouse model by driving the accumulation of Endothelin A receptor (ETAR)-positive CD11b cells in the skin—a novel category of pro-tumor inflammatory identified in this study. These findings are clinically relevant, as the number of IL27RA-positive cells in the stroma is highly related to tumor de-differentiation in patients with squamous cell carcinomas. PMID:27738312

Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades.

PubMed

Subedi, Lalita; Lee, Taek Hwan; Wahedi, Hussain Mustatab; Baek, So-Hyeon; Kim, Sun Yeou

2017-01-01

The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF- κ B-TNF- α /IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes.

Effect of Sodium Arsenite on Mouse Skin Carcinogenesis.

PubMed

Palmieri, Mónica A; Molinari, Beatriz L

2015-07-01

Arsenic is carcinogenic in human beings, and environmental exposure to arsenic is a public health issue that affects large populations worldwide. Thus, studies are needed to determine the mode of action of arsenic and prevent harmful effects arising from arsenic intake. The present study assessed the influence of sodium arsenite (As(3+)) on potentially carcinogenic processes that are either pre-existing or concomitant with chronic intake of water containing As(3+). Experiments using SenCar mice were designed to evaluate the effect of chronic administration of As(3+) (2, 20, or 200 mg of As(3+)/L) in drinking water that overlapped to varying degrees with a 2-stage carcinogenesis protocol carried out over 9 months. The results showed a time-dependent pattern. During early stages of carcinogenesis (6-12 weeks), animals exposed to As(3+) and the carcinogenesis protocol showed increased numbers of tumors compared to control animals. During late carcinogenesis (16-30 weeks), the number of tumors stabilized to below control values, but the tumors showed increased malignancy. These findings indicate that the outcomes of the 2-stage skin carcinogenesis protocol are modified by the presence of arsenite in drinking water, which increases the rate of carcinoma development. © 2015 by The Author(s).

The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC)

PubMed Central

Reichrath, Jörg; Reichrath, Sandra

2013-01-01

Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body’s requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53-mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin`s vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives. PMID:24494041

Salidroside suppresses solar ultraviolet-induced skin inflammation by targeting cyclooxygenase-2.

PubMed

Wu, Dan; Yuan, Ping; Ke, Changshu; Xiong, Hua; Chen, Jingwen; Guo, Jinguang; Lu, Mingmin; Ding, Yanyan; Fan, Xiaoming; Duan, Qiuhong; Shi, Fei; Zhu, Feng

2016-05-03

Solar ultraviolet (SUV) irradiation causes skin disorders such as inflammation, photoaging, and carcinogenesis. Cyclooxygenase-2 (COX-2) plays a key role in SUV-induced skin inflammation, and targeting COX-2 may be a strategy to prevent skin disorders. In this study, we found that the expression of COX-2, phosphorylation of p38 or JNKs were increased in human solar dermatitis tissues and SUV-irradiated human skin keratinocyte HaCaT cells and mouse epidermal JB6 Cl41 cells. Knocking down COX-2 inhibited the production of prostaglandin E2 (PGE2), the phosphorylation of p38 or JNKs in SUV-irradiated cells, which indicated that COX-2 is not only the key enzyme for PGs synthesis, but also an upstream regulator of p38 or JNKs after SUV irradiation. The virtual ligand screening assay was used to search for natural drugs in the Chinese Medicine Database, and indicated that salidroside might be a COX-2 inhibitor. Molecule modeling indicated that salidroside can directly bind with COX-2, which was proved by in vitro pull-down binding assay. Ex vivo studies showed that salidroside has no toxicity to cells, and inhibits the production of PGE2, phosphorylation of p38 or JNKs, and secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) caused by SUV irradiation. In vivo studies demonstrated that salidroside attenuates the skin inflammation induced by SUV. In brief, our data provided the evidences for the protective role of salidroside against SUV-induced inflammation by targeting COX-2, and salidroside might be a promising drug for the treatment of SUV-induced skin inflammation.

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

PubMed

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.

Division of Biological and Medical Research annual technical report 1982

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenthal, M.W.

1983-05-01

This report summarizes research during 1982 in the Division of Biological and Medical Research, Argonne National Laboratory. Studies in Carcinogenesis address mechanisms of chemical and radiation carcinogenesis including the processes of tumor initiation and promotion. The studies employ rat liver and mouse skin models as well as human rodent cell culture systems. The use of liposomes for metal mobilization is also explored. Low Level Radiation studies include delineation of the hematopoietic and other responses of dogs to continuous low level gamma irradiation, comparison of lifetime effects in mice of low level neutron and gamma irradiation, and study of the geneticmore » effects of high LET radiation. Molecular Biology research develops two-dimensional electrophoresis systems for diagnosis and detection of cancer and other diseases. Fundamental structural and biophysical investigations of immunoglobulins and other key proteins are included, as are studies of cell growth, and of molecular and cellular effects of solar uv light. Research in Toxicology uses cellular, physiological, whole animal, and chronobiological end points and chemical separations to elucidate mechanisms and evaluate hazards of coal conversion by-products, actinides, and toxic metals. The final sections cover support facilities, educational activities, seminars, staff talks, staff, and funding agencies.« less

Time-Restricted Feeding Shifts the Skin Circadian Clock and Alters UVB-Induced DNA Damage.

PubMed

Wang, Hong; van Spyk, Elyse; Liu, Qiang; Geyfman, Mikhail; Salmans, Michael L; Kumar, Vivek; Ihler, Alexander; Li, Ning; Takahashi, Joseph S; Andersen, Bogi

2017-08-01

The epidermis is a highly regenerative barrier protecting organisms from environmental insults, including UV radiation, the main cause of skin cancer and skin aging. Here, we show that time-restricted feeding (RF) shifts the phase and alters the amplitude of the skin circadian clock and affects the expression of approximately 10% of the skin transcriptome. Furthermore, a large number of skin-expressed genes are acutely regulated by food intake. Although the circadian clock is required for daily rhythms in DNA synthesis in epidermal progenitor cells, RF-induced shifts in clock phase do not alter the phase of DNA synthesis. However, RF alters both diurnal sensitivity to UVB-induced DNA damage and expression of the key DNA repair gene, Xpa. Together, our findings indicate regulation of skin function by time of feeding and emphasize a link between circadian rhythm, food intake, and skin health. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Photochemoprotective effect of a fraction of a partially purified extract of Byrsonima crassifolia leaves against UVB-induced oxidative stress in fibroblasts and hairless mice.

PubMed

de Souza, Rebeca Oliveira; de Assis Dias Alves, Geórgia; Aguillera, Ana Luiza Scarano; Rogez, Hervé; Fonseca, Maria José Vieira

2018-01-01

Ultraviolet B (UVB) irradiation increases the risk of various skin disorders, leading to inflammation and oxidative stress and thereby increasing the risk of skin photoaging and carcinogenesis. The use of photochemoprotectors such as natural products with antioxidant and anti-inflammatory properties represents a strategy for preventing UVB-induced skin damage. We investigated the photochemoprotective effect of a fraction of a partially purified extract of Byrsonima crassifolia leaves (BCF) on fibroblasts and hairless mice exposed to UVB radiation. The mixture of phenolic compounds in BCF prevented the decrease in reduced glutathione (GSH) levels in fibroblast cultures induced by UVB radiation more than some of their individual standards ((+)-catechin (CAT), epigallocatechin gallate and quercetin 3-O-β-d-glucopyranoside). Prepared gel formulations increased skin antioxidant activity, and BCF components and the CAT standard were retained in the HRS/J hairless mice epidermis 2h after application. Topical treatment with the BCF or CAT formulations (1%) significantly reduced the decrease in GSH levels and decreased myeloperoxidase activity and the secretion of pro-inflammatory cytokines IL-1β and IL-6 induced by UVB radiation (P<0.05), indicating that both BCF and CAT had anti-inflammatory effects. BCF inhibited UVB-induced metalloproteinase (MMP)-9 secretion/activity, whereas CAT had no effect on MMP-9 activity in the skin of treated animals. These results therefore suggest that BCF can be used as a photochemoprotective agent and antioxidant in the prevention/treatment of inflammation and oxidative stress of the skin induced by UVB radiation. Copyright © 2017 Elsevier B.V. All rights reserved.

Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System.

PubMed

Ben Yehuda Greenwald, Maya; Frušić-Zlotkin, Marina; Soroka, Yoram; Ben Sasson, Shmuel; Bitton, Ronit; Bianco-Peled, Havazelet; Kohen, Ron

2017-01-01

Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf 2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases.

Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System

PubMed Central

Ben Yehuda Greenwald, Maya; Frušić-Zlotkin, Marina; Soroka, Yoram; Ben Sasson, Shmuel; Bitton, Ronit; Bianco-Peled, Havazelet

2017-01-01

Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases. PMID:28757910

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.

PubMed

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.

Determination of minimal erythema dose and anomalous reactions to UVA radiation by skin phototype.

PubMed

Pérez Ferriols, A; Aguilera, J; Aguilera, P; de Argila, D; Barnadas, M A; de Cabo, X; Carrrascosa, J M; de Gálvez Aranda, M V; Gardeazábal, J; Giménez-Arnau, A; Lecha, M; Lorente, J; Martínez-Lozano, J A; Rodríguez Granados, M T; Sola, Y; Utrillas, M P

2014-10-01

Phototesting is a technique that assesses the skin's sensitivity to UV radiation by determining the smallest dose of radiation capable of inducing erythema (minimal erythema dose [MED]) and anomalous responses to UV-A radiation. No phototesting protocol guidelines have been published to date. This was a multicenter prospective cohort study in which 232 healthy volunteers were recruited at 9 hospitals. Phototests were carried out with solar simulators or fluorescent broadband UV-B lamps. Each individual received a total of 5 or 6 incremental doses of erythemal radiation and 4 doses of UV-A radiation. The results were read at 24hours. At hospitals where solar simulators were used, the mean (SD) MED values were 23 (8), 28 (4), 35 (4), and 51 (6) mJ/cm(2) for skin phototypes i to iv, respectively. At hospitals where broadband UV-B lamps were used, these values were 28 (5), 32 (3), and 34 (5) mJ/cm(2) for phototypes ii to iv, respectively. MED values lower than 7, 19, 27, and 38 mJ/cm(2) obtained with solar simulators were considered to indicate a pathologic response for phototypes I to IV, respectively. MED values lower than 18, 24, and 24mJ/cm(2) obtained with broadband UV-B lamps were considered to indicate a pathologic response for phototypes ii to iv, respectively. No anomalous responses were observed at UV-A radiation doses of up to 20J/cm(2). Results were homogeneous across centers, making it possible to standardize diagnostic phototesting for the various skin phototypes and establish threshold doses that define anomalous responses to UV radiation. Copyright © 2014 Elsevier España, S.L.U. y AEDV. All rights reserved.

Poly(I:C) induces expressions of MMP-1, -2, and -3 through various signaling pathways including IRF3 in human skin fibroblasts.

PubMed

Yao, Cheng; Lee, Dong Hun; Oh, Jang-Hee; Kim, Min-Kyoung; Kim, Kyu Han; Park, Chi-Hyun; Chung, Jin Ho

2015-10-01

Ultraviolet (UV) irradiation can result in premature skin aging (photoaging) which is characterized by decreased expression of collagen and increased expression of matrix metalloproteinases (MMPs). Double-stranded RNAs (dsRNAs) can be generated at various conditions including virally infected cells or UV-damaged skin cells. Recent studies have shown that a synthetic dsRNA, polyinosinic-polycytidylic acid (poly(I:C)), can reduce procollagen expression in human skin fibroblasts. However, little is known about the effect of poly(I:C) on the expression of MMPs in skin fibroblasts and its underlying mechanisms. We examined the effect of poly(I:C) on MMP-1, -2, and -3 expressions in human skin fibroblasts. Then, we further explored the underlying signaling pathways involved in the processes. Human skin fibroblasts were treated with poly(I:C) for the indicated times in the presence or the absence of various chemical inhibitors or small interfering RNAs (siRNAs) at the indicated concentrations. Protein and mRNA levels of various target molecules were examined by Western blotting and quantitative real-time PCR, respectively. Poly(I:C) induced MMP-1, -2, and -3 expressions, which were dependent on TLR3. Poly(I:C) also induced activations of the mitogen-activated protein kinases (MAPKs), the nuclear factor-kappaB (NF-κB) and the interferon regulatory factor 3 (IRF3) pathways. By using specific inhibitors, we found that poly(I:C)-induced expressions of MMP-1, -2, and -3 were differentially regulated by these signaling pathways. In particular, we found that the inhibition of IRF3 signaling pathways attenuated poly(I:C)-induced expressions of all the three MMPs. Our data show that the expressions of MMP-1, -2, and -3 are induced by poly(I:C) through various signaling pathways in human skin fibroblasts and suggest that TLR3 and/or IRF3 may be good targets for regulating the expressions of MMP-1, -2, and -3 induced by dsRNAs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Empirical Modeling of Physiochemical Immune Response of Multilayer Zinc Oxide Nanomaterials under UV Exposure to Melanoma and Foreskin Fibroblasts

NASA Astrophysics Data System (ADS)

Fakhar-E-Alam, Muhammad; Akram, M. Waseem; Iqbal, Seemab; Alimgeer, K. S.; Atif, M.; Sultana, K.; Willander, M.; Wang, Zhiming M.

2017-04-01

Carcinogenesis is a complex molecular process starting with genetic and epigenetic alterations, mutation stimulation, and DNA modification, which leads to proteomic adaptation ending with an uncontrolled proliferation mechanism. The current research focused on the empirical modelling of the physiological response of human melanoma cells (FM55P) and human foreskin fibroblasts cells (AG01518) to the multilayer zinc oxide (ZnO) nanomaterials under UV-A exposure. To validate this experimental scheme, multilayer ZnO nanomaterials were grown on a femtotip silver capillary and conjugated with protoporphyrin IX (PpIX). Furthermore, PpIX-conjugated ZnO nanomaterials grown on the probe were inserted into human melanoma (FM55P) and foreskin fibroblasts cells (AG01518) under UV-A light exposure. Interestingly, significant cell necrosis was observed because of a loss in mitochondrial membrane potential just after insertion of the femtotip tool. Intense reactive oxygen species (ROS) fluorescence was observed after exposure to the ZnO NWs conjugated with PpIX femtotip model under UV exposure. Results were verified by applying several experimental techniques, e.g., ROS detection, MTT assay, and fluorescence spectroscopy. The present work reports experimental modelling of cell necrosis in normal human skin as well as a cancerous tissue. These obtained results pave the way for a more rational strategy for biomedical and clinical applications.

Modulation of in vitro transformation and the early and late modes of DNA replication of uv-irradiation Syrian hamster cells by caffeine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Doniger, J.; DiPaolo, J.A.

1981-09-01

The effect of caffeine on post-uv DNA replication was studied to determine its relevance to carcinogenesis. The level of uv-induced transformed colonies of Syrian hamster embryo cells (HEC) was increased up to fivefold when caffeine was added to cells between 0 and 6 h post-uv. The greatest increase was observed when the interval between uv irradiation and caffeine addition was 4 h. Two modes of DNA replication occurred after uv irradiation. During the early mode (0 to 3 h post-uv) the size of nascent strands, as measured by alkaline sucrose sedimentation, was smaller than those in nonirradiated cells, whereas duringmore » the late mode they recovered to normal size. Caffeine inhibited the rate of elongation of nascent strands during the early mode. When caffeine was added immediately after uv irradiation, the conversion of the early mode to the late mode was inhibited. Studies on the effects of caffeine have now been extended to the late mode. While caffeine has little effect with the fd elements beginning from the 10th day after irradiation is connected with their proliferation but not with the migration out from lymphoid organs.« less

Regulation of miR-21 expression in human melanoma via UV-ray-induced melanin pigmentation.

PubMed

Lin, Kuan-Yu; Chen, Chien-Min; Lu, Cheng-You; Cheng, Chun-Yuan; Wu, Yu-Hsin

2017-08-01

Excessive environmental ultraviolet (UV) radiation produces genetic mutations that can lead to skin cancer. This study was designed to assess the potential inhibitory activity of microRNA-21 (miR-21) on the UV irradiation-stimulated melanogenesis signal pathway in melanoma cells. The molecular mechanism of miR-21-induced inhibitory activity on UV-ray-stimulated melanogenesis-regulating proteins was examined in A375.S2 human melanoma and B16F10 mouse melanoma cells. UV irradiation for 30 min induced melanogenesis signal pathway by increasing melanin production and the number of A375.S2 cells. Similarly, UV radiation increased the expression of α-melanocyte-stimulating hormone (α-MSH) protein and decreased the melanogenesis-regulating signal, such as EGFR and Akt phosphorylation. Notably, miR-21 overexpression in UV-ray-stimulated A375.S2 cells decreased α-MSH expression and increased EGFR and Akt phosphorylation levels. Furthermore, miR-21 on UV-ray- induced melanogenesis was down-regulated by the Akt inhibitor and the EGFR inhibitor (Gefitinib). Results suggest that the suppressive activity of miR-21 on UV-ray-stimulated melanogenesis may involve the down-regulation of α-MSH and the activation in both of EGFR and Akt. © 2017 Wiley Periodicals, Inc.

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

PubMed

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.

Abnormal ultraviolet mutagenic spectrum in plasmid DNA replicated in cultured fibroblasts from a patient with the skin cancer-prone disease, xeroderma pigmentosum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seetharam, S.; Protic-Sabljic, M.; Seidman, M.M.

1987-12-01

A shuttle vector plasmid, pZ189, was utilized to assess the types of mutations that cells from a patient with xeroderma pigmentosum, complementation group D, introduce into ultraviolet (UV) damaged, replicating DNA. Patients with xeroderma pigmentosum have clinical and cellular UV hypersensitivity, increased frequency of sun-induced skin cancer, and deficient DNA repair. In comparison to UV-treated pZ189 replicated in DNA repair-proficient cells, there were fewer surviving plasmids, a higher frequency of plasmids with mutations, fewer plasmids with two or more mutations in the marker gene, and a new mutagenic hotspot. The major type of base substitution mutation was the G:C tomore » A:T transition with both cell lines. These results, together with similar findings published earlier with cells from a xeroderma pigmentosum patient in complementation group A, suggest that isolated G:C to A:T somatic mutations may be particularly important in generation of human skin cancer by UV radiation.« less

Chemical and Molecular Biological Aspects of Alkylhydrazine-Induced Carcinogenesis in Human Cells in Vitro. Revised

DTIC Science & Technology

1984-04-01

weights using the following phage DNA markers : lambda, T2 and T7. The number of alkaline labile sites (breaks due to apurinic sites and phosphotriesters...exhibit cell invasiveness in chick embryo skin, human malignancy specific cell- surface antigenic determinants (19), and produce tumors in pre...they eluted from the column, were identified by co-chromatographed markers , (Chart 2). When randomly proliferating cells were treated with either 1,1-DMH

Gromwell (Lithospermum erythrorhizon) root extract protects against glycation and related inflammatory and oxidative stress while offering UV absorption capability.

PubMed

Glynn, Kelly M; Anderson, Penny; Fast, David J; Koedam, James; Rebhun, John F; Velliquette, Rodney A

2018-06-15

Glycation and advanced glycation endproducts (AGE) damage skin which is compounded by AGE-induced oxidative stress and inflammation. Lip and facial skin could be susceptible to glycation damage as they are chronically stressed. As Gromwell (Lithospermum erythrorhizon) root (GR) has an extensive traditional medicine history that includes providing multiple skin benefits, our objective was to determine if GR extract and its base naphthoquinone, shikonin, might protect skin by inhibiting glycation, increasing oxidative defenses, suppressing inflammatory responses, and offering ultraviolet (UV) absorptive potential in lip and facial cosmetic matrices. We show GR extract and shikonin dose-dependently inhibited glycation and enhanced oxidative defenses through nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) activation. Inflammatory targets, nuclear factor kappa light chain enhancer of activated B cells (NFκB) and tumor necrosis factor alpha (TNFα), were suppressed by GR extract and shikonin. Glyoxalase 1 (GLO1) and glutathione synthesis genes were significantly upregulated by GR extract and shikonin. GR extract boosted higher wavelength UV absorption in select cosmetic matrices. Rationale for the use of GR extract and shikonin are supported by our research. By inhibiting glycation, modulating oxidative stress, suppressing inflammation, and UV-absorptive properties, GR extract and shikonin potentially offer multiple skin benefits. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Comparative study of carotenoids, catalase and radical formation in human and animal skin.

PubMed

Haag, S F; Bechtel, A; Darvin, M E; Klein, F; Groth, N; Schäfer-Korting, M; Bittl, R; Lademann, J; Sterry, W; Meinke, M C

2010-01-01

Animal skin is widely used in dermatological free radical research. Porcine ear skin is a well-studied substitute for human skin. The use of bovine udder skin is rare but its high carotenoid content makes it particularly appropriate for studying the redox state of the skin. Yet, information on the suitability of animal skin for the study of external hazard effects on the redox state of human skin has been lacking. In this study, we investigated the activity of the antioxidant enzyme catalase and the carotenoid content defining the redox status as well as UV-induced radical formation of human, porcine ear and bovine udder skin ex vivo. In human skin only low levels of radical formation were detected following UV irradiation, whereas bovine skin contains the highest amount of carotenoids but the lowest amount of catalase. Porcine ear skin does not exhibit a carotenoid signal but its catalase activity is close to human skin. Therefore, radical formation can neither be correlated to the amount of catalase nor to the amount of carotenoids in the skin. All skin types can be used for electron paramagnetic resonance-based detection of radicals, but porcine skin was found to be the most suitable type. Copyright 2010 S. Karger AG, Basel.

[Ultraviolet radiation, tobacco smoke and estrogens pathways of influence on skin aging; capabilities of prevention].

PubMed

Wojas-Pelc, Anna; Sułowicz, Joanna; Nastałek, Magdalena

2008-01-01

Aging refers to the hole human body including the skin, but here it is usually better seen by milieu, repeatedly burdens life quality. There are many theories explaining the process of human aging, but its reasons, irrespectively of their criteria, are numerous and affect one another. Skin aging just like the entire body depends on the influence of genetics, environmental and hormonal factors. Ultraviolet radiation and tobacco smoking have confirmed influence on skin aging. The role of hormonal disorders, particularly estrogens are also underlined. Mechanisms of skin aging induced by UV radiation, tobacco smoke and estrogens are similar and included unfavourable effects of oxidative stress (free radicals) and also disturbances of the TGF beta pathway. Data of many clinical studies proved that avoiding sun and smoking, nucleic acids diet, antioxidant supplementation, everyday use of UV filter, moisturizers, topical use of antioxidants, retinoid derivatives and flavonoids have proved protective the influence to multidirectional process of skin aging.

Natural and Sun-Induced Aging of Human Skin

PubMed Central

Rittié, Laure; Fisher, Gary J.

2015-01-01

With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases. PMID:25561721

Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action.

PubMed

Chilampalli, Chandeshwari; Guillermo, Ruth; Zhang, Xiaoying; Kaushik, Radhey S; Young, Alan; Zeman, David; Hildreth, Michael B; Fahmy, Hesham; Dwivedi, Chandradhar

2011-10-20

Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development. UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle. Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice.Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells. Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer.

Effects of magnolol on UVB-induced skin cancer development in mice and its possible mechanism of action

PubMed Central

2011-01-01

Background Magnolol, a plant lignan isolated from the bark and seed cones of Magnolia officinalis, has been shown to have chemopreventive effects on chemically-induced skin cancer development. The objectives of this investigation are to study the anticarcinogenic effects of magnolol on UVB-induced skin tumor development in SKH-1 mice, a model relevant to humans, and determine the possible role of apoptosis and cell cycle arrest involved in the skin tumor development. Methods UVB-induced skin carcinogenesis model in SKH-1 mice was used for determining the preventive effects of magnolol on skin cancer development. Western blottings and flow cytometric analysis were used to study the effects of magnolol on apoptosis and cell cycle. Results Magnolol pretreated groups (30, 60 μ g) before UVB treatments (30 mJ/cm2, 5 days/week) resulted in 27-55% reduction in tumor multiplicity as compared to control group in SKH-1 mice. Magnolol pretreatment increased the cleavage of caspase-8 and poly-(-ADP-ribose) polymerase (PARP), increased the expression of p21, a cell cycle inhibitor, and decreased the expression of proteins involved in the G2/M phase of cell cycle in skin samples from SKH-1 mice. Treatment of A431 cells with magnolol decreased cell viability and cell proliferation in a concentration dependent manner. Magnolol induced G2/M phase cell cycle arrest in A431 cells at 12 h with a decreased expression of cell cycle proteins such as cyclin B1, cyclin A, CDK4, Cdc2 and simultaneous increase in the expression of Cip/p21, a cyclin-dependent kinase inhibitor. Magnolol induced apoptosis in vivo and in vitro with an increased cleavage of caspase-8 and PARP. Phospho-signal transducers and activators of transcription 3 (Tyr705), B-Raf, p-MEK, and p-AKT were down-regulated, whereas phosphorylation of ERK was induced by magnolol in A431 cells. Conclusions Magnolol pretreatments prevent UVB-induced skin cancer development by enhancing apoptosis, causing cell cycle arrest at G2/M phase, and affecting various signaling pathways. Magnolol could be a potentially safe and potent anticarcinogenic agent against skin cancer. PMID:22014088

Synthesis and biological evaluation of sulfur-containing cinnamate and salicylate derivatives.

PubMed

Chiang, Chih-Chia; Chang, Tsu-Chung; Tsai, Hou-Jen; Hsu, Ling-Yih

2008-03-01

UV irradiation induced formation of reactive oxygen radical species and matrix metalloproteinases (MMPs) are thought to be involved in photo-damage to the skin. MMP-1 is the major collagenolytic enzyme responsible for collagen destruction in skin tissue. To develop new anti-photoaging agents, a series of 2,2'-dithiocinnamate derivatives and 2,2'-dithio or 2-thiobenzoate derivatives were designed and synthesized. The biological activities of the synthesized compounds were assayed for ABTS [2,2'-azinobis-(3-ethyl-benzo-thiazoline-6-sulfonic acid)] radical scavenging activity, MMP-1 inhibitory activity, and cytotoxicity to human dermal fibroblast cells. Compounds with potential of resistance to UV irradiation were identified. These compounds are expected to be useful for preventing photo-damage to the skin.

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing.

PubMed

Li, Yuanying; Wang, Yu; Zhang, Wei; Jiang, Leiwei; Zhou, Wenming; Liu, Zhi; Li, Shijun; Lu, Hongguang

2018-02-28

Seborrhoeic keratosis is an age-related skin disease. Amyloid precursor protein (APP) plays an important role in the pathogenesis of age-related Alzheimer's disease. The aim of this study was to elucidate the expression characteristics of APP in seborrhoeic keratosis tissues (n = 50), and explore whether the production of APP is related to the onset of seborrhoeic keratosis and skin ageing, including ultraviolet (UV)-induced ageing, as observed in normal skin (n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products (i.e. amyloid-β42) were more highly expressed in seborrhoeic keratosis than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase (i.e. β-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group (61-85 years) was greater than that in the younger age group (41-60 years) in seborrhoeic keratosis tissues (p<0.05). APP expression correlated positively with age in epidermis (p<0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of seborrhoeic keratosis and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of seborrhoeic keratosis and skin ageing.

Invited Review Vitamin D and skin cancer†

PubMed Central

Burns, Erin M.; Elmets, Craig A.; Yusuf, Nabiha

2014-01-01

Vitamin D signaling plays a key role in various important processes, including cellular proliferation, differentiation, and apoptosis, immune regulation, hormone secretion, and skeletal health. Further, vitamin D production and supplementation have been shown to exert protective effects via an unknown signaling mechanism involving the vitamin D receptor (VDR) in several diseases and cancer types, including skin cancer. With over 3.5 million new diagnoses in 2 million patients annually, skin cancer is the most common cancer type in the United States. While ultraviolet B (UVB) radiation is the main etiologic factor for non-melanoma skin cancer (NMSC), UVB also induces cutaneous vitamin D production. This paradox has been the subject of contradictory findings in the literature in regards to amount of sun exposure necessary for appropriate vitamin D production, as well as any beneficial or detrimental effects of vitamin D supplementation for disease prevention. Further clinical and epidemiological studies are necessary to elucidate the role of vitamin D in skin carcinogenesis. PMID:25378147

Resveratrol-Enriched Rice Attenuates UVB-ROS-Induced Skin Aging via Downregulation of Inflammatory Cascades

PubMed Central

Lee, Taek Hwan; Wahedi, Hussain Mustatab; Baek, So-Hyeon

2017-01-01

The skin is the outermost protective barrier between the internal and external environments in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of skin aging. UVB radiation penetrates the skin and induces ROS production that activates three major skin aging cascades: matrix metalloproteinase- (MMP-) 1-mediated aging; MAPK-AP-1/NF-κB-TNF-α/IL-6, iNOS, and COX-2-mediated inflammation-induced aging; and p53-Bax-cleaved caspase-3-cytochrome C-mediated apoptosis-induced aging. These mechanisms are collectively responsible for the wrinkling and photoaging characteristic of UVB-induced skin aging. There is an urgent requirement for a treatment that not only controls these pathways to prevent skin aging but also avoids the adverse effects often encountered when applying bioactive compounds in concentrated doses. In this study, we investigated the efficacy of genetically modified normal edible rice (NR) that produces the antiaging compound resveratrol (R) as a treatment for skin aging. This resveratrol-enriched rice (RR) overcomes the drawbacks of R and enhances its antiaging potential by controlling the abovementioned three major pathways of skin aging. RR does not exhibit the toxicity of R alone and promisingly downregulates the pathways underlying UVB-ROS-induced skin aging. These findings advocate the use of RR as a nutraceutical for antiaging purposes. PMID:28900534

[Light protection for xeroderma pigmentosum].

PubMed

Ettinger, M; Berneburg, M

2017-05-01

Xeroderma pigmentosum is a rare autosomal recessive disorder which is caused by germinal mutations responsible for the repair of ultraviolet (UV) radiation-induced DNA lesions. It is characterized by hypersensitivity to UV radiation, poikiloderma, ocular surface disease, and in some patients pronounced sunburn and neurological disease. Patients have a very high risk of developing ocular and skin cancer on exposed body sites. No cure is available for these patients except complete protection from all types of UV radiation.

Plasma Rich in Growth Factors Enhances Wound Healing and Protects from Photo-oxidative Stress in Dermal Fibroblasts and 3D Skin Models.

PubMed

Anitua, Eduardo; Pino, Ander; Jaen, Pedro; Orive, Gorka

2016-01-01

Optimal skin repair has been a desired goal for many researchers. Recently, plasma rich in growth factors (PRGF) has gained importance in dermatology proving it is beneficial effects in wound healing and cutaneous regeneration. The anti-fibrotic, pro-contractile and photo-protective effect of PRGF on dermal fibroblasts and 3D skin models has been evaluated. The effect against TGFβ1 induced myofibroblast differentiation was tested. Cell contractile activity over collagen gel matrices was analyzed and the effect against UV derived photo-oxidative stress was assessed. The effectiveness of PRGF obtained from young aged and middle aged donors was compared. Furthermore, 3D organotypic skin explants were used as human skin models with the aim of analyzing ex vivo cutaneous preventive and regenerative photo-protection after UV exposure. TGFβ1 induced myofibroblast levels decreased significantly after treatment with PRGF while the contractile activity increased compared to the control group. After UV irradiation, cell survival was promoted while apoptotic and ROS levels were noticeably reduced. Photo-exposed 3D explants showed higher levels of metabolic activity and lower levels of necrosis, cell damage, irritation and ROS formation when treated with PRGF. The histological integrity and connective tissue fibers showed lower signals of photodamage among PRGF injected skin models. No significant differences for the assessed biological outcomes were observed when PRGF obtained from young aged and middle aged donors were compared. These findings suggest that this autologous approach might be useful for antifibrotic wound healing and provide an effective protection against sun derived photo-oxidative stress regardless the age of the patient.

2,6-Dithiopurine blocks toxicity and mutagenesis in human skin cells exposed to sulfur mustard analogues, 2-chloroethyl ethyl sulfide and 2-chloroethyl methyl sulfide.

PubMed

Powell, K Leslie; Boulware, Stephen; Thames, Howard; Vasquez, Karen M; MacLeod, Michael C

2010-03-15

Sulfur mustard (bis-(2-chloroethyl)sulfide) is a well-known chemical warfare agent that induces debilitating cutaneous toxicity in exposed individuals. It is also known to be carcinogenic and mutagenic because of its ability to damage DNA via electrophilic attack. We previously showed that a nucleophilic scavenger, 2,6-dithiopurine (DTP), reacts chemically with several electrophilic carcinogens, blocking DNA damage in vitro and in vivo and abolishing tumor formation in a two-stage mouse skin carcinogenesis model. To assess the potential of DTP as an antagonist of sulfur mustard, we have utilized monofunctional chemical analogues of sulfur mustard, 2-chloroethyl ethyl sulfide (CEES) and 2-chloroethyl methyl sulfide (CEMS), to induce toxicity and mutagenesis in a cell line, NCTC2544, derived from a human skin tumor. We show that DTP blocks cytotoxicity in CEMS- and CEES-treated cells when present at approximately equimolar concentration. A related thiopurine, 9-methyl-6-mercaptopurine, is similarly effective. Correlated with this, we find that DTP is transported into these cells and that adducts between DTP and CEES are found intracellularly. Using a shuttle vector-based mutagenesis system, which allows enumeration of mutations induced in the skin cells by a blue/white colony screen, we find that DTP completely abolishes the mutagenesis induced by CEMS and CEES in human cells.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pratheeshkumar, Poyil; Son, Young-Ok; Wang, Xin

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 indicatemore » 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 inhibited UVB-induced elevated proinflammatory cytokine level. • C3G inhibited UVB-induced p38 MAP kinase signaling. • C3G inhibited UVB-induced NF-κB activation.« less

New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals: In Vitro and In Vivo Studies and the Underlying Mechanisms.

PubMed

Singh, Madhulika; Suman, Shankar; Shukla, Yogeshwer

2014-01-01

Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo models and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer.

Myricetin suppresses UVB-induced wrinkle formation and MMP-9 expression by inhibiting Raf

PubMed Central

Jung, Sung Keun; Lee, Ki Won; Kim, Ho Young; Oh, Mi Hyun; Byun, Sanguine; Lim, Sung Hwan; Heo, Yong-Seok; Kang, Nam Joo; Bode, Ann M.; Dong, Zigang; Lee, Hyong Joo

2010-01-01

Chronic exposure to solar ultraviolet (UV) light causes skin photoaging. Many studies have shown that naturally occurring phytochemicals have anti-photoaging effects, but their direct target molecule(s) and mechanism(s) remain unclear. We found that myricetin, a major flavonoid in berries and red wine, inhibited wrinkle formation in mouse skin induced by chronic UVB irradiation (0.18 J/cm2, 3 days/wk for 15 wk). Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. Myricetin appeared to exert its anti-aging effects by suppressing UVB-induced Raf kinase activity and subsequent attenuation of UVB-induced phosphorylation of MEK and ERK in mouse skin. In vitro and in vivo pull-down assays revealed that myricetin bound with Raf in an ATP-noncompetitive manner. Overall, these results indicate that myricetin exerts potent anti-photoaging activity by regulating MMP-9 expression through the suppression of Raf kinase activity. PMID:20093107

Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin

PubMed Central

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

2017-01-01

The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of bixin-induced antioxidant and anti-inflammatory effects. In addition, bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination. PMID:29258247

Skin protection against UVA-induced iron damage by multiantioxidants and iron chelating drugs/prodrugs.

PubMed

Reelfs, Olivier; Eggleston, Ian M; Pourzand, Charareh

2010-03-01

In humans, prolonged sunlight exposure is associated with various pathological states. The continuing drive to develop improved skin protection involves not only approaches to reduce DNA damage by solar ultraviolet B (UVB) but also the development of methodologies to provide protection against ultraviolet A (UVA), the oxidising component of sunlight. Furthermore identification of specific cellular events following ultraviolet (UV) irradiation is likely to provide clues as to the mechanism of the development of resulting pathologies and therefore strategies for protection. Our discovery that UVA radiation, leads to an immediate measurable increase in 'labile' iron in human skin fibroblasts and keratinocytes provides a new insight into UVA-induced skin damage, since iron is a catalyst of biological oxidations. The main purpose of this overview is to bring together some of the new findings related to mechanisms underlying UVA-induced iron release and to discuss novel approaches based on the use of multiantioxidants and light-activated caged-iron chelators for efficient protection of skin cells against UVA-induced iron damage.

Interferon-Gamma Promotes UV-Induced Melanoma in Mice | Center for Cancer Research

Cancer.gov

Scientists have made an unanticipated discovery in mice that interferon-gamma, a type of protein primarily used by the immune system for intercellular communication, acts as a promoter for the deadly form of skin cancer known as melanoma. This finding resulted from a series of experiments designed to understand how solar ultraviolet (UV) radiation causes melanoma. This study

Resistance of a lizard (the green anole, Anolis carolinensis; Polychridae) to ultraviolet radiation-induced immunosuppression

USGS Publications Warehouse

Cope, R.B.; Fabacher, D.L.; Lieske, C.; Miller, C.A.

2001-01-01

The green anole (Anolis carolinensis) is the most northerly distributed of its Neotropical genus. This lizard avoids a winter hibernation phase by the use of sun basking behaviors. Inevitably, this species is exposed to high doses of ambient solar ultraviolet radiation (UVR). Increases in terrestrial ultraviolet-B (UV-B) radiation secondary to stratospheric ozone depletion and habitat perturbation potentially place this species at risk of UVR-induced immunosuppression. Daily exposure to subinflammatory UVR (8 kJ/m2/day UV-B, 85 kJ/m2/day ultraviolet A [UV-A]), 6 days per week for 4 weeks (total cumulative doses of 192 kJ/m2 UV-B, 2.04 × 103 kJ/m2 UV-A) did not suppress the anole's acute or delayed type hypersensitivity (DTH) response to horseshoe crab hemocyanin. In comparison with the available literature UV-B doses as low as 0.1 and 15.9 kJ/m2 induced suppression of DTH responses in mice and humans, respectively. Exposure of anoles to UVR did not result in the inhibition of ex vivo splenocyte phagocytosis of fluorescein labeled Escherichia coli or ex vivo splenocyte nitric oxide production. Doses of UV-B ranging from 0.35 to 45 kJ/m2 have been reported to suppress murine splenic/peritoneal macrophage phagocytosis and nitric oxide production. These preliminary studies demonstrate the resistance of green anoles to UVR-induced immunosuppression. Methanol extracts of anole skin contained two peaks in the ultraviolet wavelength range that could be indicative of photoprotective substances. However, the resistance of green anoles to UVR is probably not completely attributable to absorption by UVR photoprotective substances in the skin but more likely results from a combination of other factors including absorption by the cutis and absorption and reflectance by various components of the dermis.

UV Radiation and the Skin

PubMed Central

D’Orazio, John; Jarrett, Stuart; Amaro-Ortiz, Alexandra; Scott, Timothy

2013-01-01

UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance. PMID:23749111

UV radiation and the skin.

PubMed

D'Orazio, John; Jarrett, Stuart; Amaro-Ortiz, Alexandra; Scott, Timothy

2013-06-07

UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

PubMed Central

Pi, Jingbo; Diwan, Bhalchandra A.; Sun, Yang; Liu, Jie; Qu, Wei; He, Yuying; Styblo, Miroslav; Waalkes, Michael P.

2009-01-01

Arsenic is a well-known human skin carcinogen but the underlying mechanisms of carcinogenesis are unclear. Transcription factor Nrf2-mediated antioxidant response represents a critical cellular defense mechanism, and emerging data suggest that constitutive activation of Nrf2 contributes to malignant phenotype. In the present study when an immortalized, non-tumorigenic human keratinocyte cell line (HaCaT) was continuously exposed to environmentally relevant level of inorganic arsenite (100 nM) for 28 weeks, malignant transformation occurred as evidenced by the formation of highly aggressive squamous cell carcinoma after inoculation into nude mice. To investigate the mechanisms involved, a broad array of biomarkers for transformation were assessed in these arsenic-transformed cells (termed As-TM). In addition to increased secretion of matrix metalloproteinase-9 (MMP-9), a set of markers for squamous differentiation and skin keratinization, including keratin-1, keratin-10, involucrin, and loricrin, were significantly elevated in As-TM cells. Furthermore, As-TM cells showed increased intracellular glutathione, elevated expression of Nrf2 and its target genes, as well as generalized apoptotic resistance. In contrast to increased basal Nrf2 activity in As-TM cells, a diminished Nrf2-mediated antioxidant response induced by acute exposure to high dose of arsenite or tert-butyl hydroxyquinone occurred. The findings that multiple biomarkers for malignant transformation observed in As-TM cells, including MMP-9 and cytokeratins, are potentially regulated by Nrf2 suggest constitutive Nrf2 activation may be involved in arsenic carcinogenesis of skin. The weakened Nrf2 activation in response to oxidative stressors observed in As-TM cells, coupled with acquired apoptotic resistance, would potentially have increased the likelihood of transmittable oxidative DNA damage and fixation of mutational/DNA damage events. PMID:18572023

Towards label-free evaluation of oxidative stress in human skin exposed to sun filters (Conference Presentation)

NASA Astrophysics Data System (ADS)

Osseiran, Sam; Wang, Hequn; Suita, Yusuke; Roider, Elisabeth; Fisher, David E.; Evans, Conor L.

2016-02-01

Skin cancer, including basal cell carcinoma, squamous cell carcinoma, and melanoma, is the most common form of cancer in North America. Paradoxically, skin cancer incidence is steadily on the rise even despite the growing use of sunscreens over the past decades. One potential explanation for this discrepancy involves the sun filters in sunscreen, which are responsible for blocking harmful ultraviolet radiation. It is proposed that these agents may produce reactive oxygen species (ROS) at the site of application, thereby generating oxidative stress in skin that gives rise to genetic mutations, which may explain the rising incidence of skin cancer. To test this hypothesis, ex vivo human skin was treated with five common chemical sun filters (avobenzone, octocrylene, homosalate, octisalate, and oxybenzone) as well as two physical sun filters (zinc oxide compounds), both with and without UV irradiation. To non-invasively evaluate oxidative stress, two-photon excitation fluorescence (2PEF) and fluorescence lifetime imaging microscopy (FLIM) of the skin samples were used to monitor levels of NADH and FAD, two key cofactors in cellular redox metabolism. The relative redox state of the skin was assessed based on the fluorescence intensities and lifetimes of these endogenous cofactors. While the sun filters were indeed shown to have a protective effect from UV radiation, it was observed that they also generate oxidative stress in skin, even in the absence of UV light. These results suggest that sun filter induced ROS production requires more careful study, especially in how these reactive species impact the rise of skin cancer.

Pinus densiflora extract protects human skin fibroblasts against UVB-induced photoaging by inhibiting the expression of MMPs and increasing type I procollagen expression.

PubMed

Jung, Hoe-Yune; Shin, Jae-Cheon; Park, Seon-Min; Kim, Na-Ri; Kwak, Wonjung; Choi, Bo-Hwa

2014-01-01

Exposure to ultraviolet (UV) light can cause skin photoaging, which is associated with upregulation of matrix metalloproteinases (MMPs) and downregulation of collagen synthesis. It has been reported that MMPs, especially MMP-1, MMP-3 and MMP-9, decrease the elasticity of the dermis by degrading collagen. In this study, we assessed the effects of Pinus densiflora extract (PDE) on photoaging and investigated its mechanism of action in human skin fibroblast (Hs68) cells after UVB exposure using real-time polymerase chain reaction, Western blot analysis, and enzymatic activity assays. PDE exhibited an antioxidant activity and inhibited elastase activities in vitro. We also found that PDE inhibited UVB-induced cytotoxicity, MMP-1 production and expression of MMP-1, -3 and -9 mRNA in Hs68 cells. In addition, PDE decreased UVB-induced MMP-2 activity and MMP-2 mRNA expression. Moreover, PDE prevented the decrease of type I procollagen mediated by exposure to UVB irradiation, an effect that is linked to the upregulation and downregulation of Smad3 and Smad7, respectively. Another effect of UV irradiation is to stimulate activator protein 1 (AP-1) activity via overexpression of c-Jun/c-Fos, which, in turn, upregulates MMP-1, -3, and -9. In this study, we found that PDE suppressed UV-induced c-Jun and c-Fos mRNA expression. Taken together, these results demonstrate that PDE regulates UVB-induced expression of MMPs and type I procollagen synthesis by inhibiting AP-1 activity and restoring impaired Smad signaling, suggesting that PDE may be useful as an effective anti-photoaging agent.

Increased blood flow and vasculature in solar lentigo.

PubMed

Hasegawa, Kiyotaka; Fujiwara, Rumiko; Sato, Kiyoshi; Park, Ji-Youn; Kim, Sang Jin; Kim, Misun; Kang, Hee Young

2016-10-01

Solar lentigo (SL) is a hallmark of ultraviolet (UV)-induced photoaged skin and growing evidence implicates blood vessels in UV-associated pigmentation. In this study, we investigated whether the vasculatures are modified in SL. Twenty-five women with facial SL were enrolled and colorimetric and blood flow studies were performed. There was a significant increase in erythema which was associated with increased blood flow in the lesional skin compared with perilesional normal skin. Immunohistochemical studies with 24 facial SL biopsies consistently revealed a significant increase in vessel density accompanied by increased levels of vascular endothelial growth factor expression. CD68 immunoreactivity was significantly higher in lesional skin suggesting increased macrophage infiltration in SL. In conclusion, SL is characterized by increased blood flow and vasculature. These findings suggest the possible influence of the characteristics of vasculature on development of SL. © 2016 Japanese Dermatological Association.

Photoprotection by pistachio bioactives in a 3-dimensional human skin equivalent tissue model.

PubMed

Chen, C-Y Oliver; Smith, Avi; Liu, Yuntao; Du, Peng; Blumberg, Jeffrey B; Garlick, Jonathan

2017-09-01

Reactive oxygen species (ROS) generated during ultraviolet (UV) light exposure can induce skin damage and aging. Antioxidants can provide protection against oxidative injury to skin via "quenching" ROS. Using a validated 3-dimensional (3D) human skin equivalent (HSE) tissue model that closely mimics human skin, we examined whether pistachio antioxidants could protect HSE against UVA-induced damage. Lutein and γ-tocopherol are the predominant lipophilic antioxidants in pistachios; treatment with these compounds prior to UVA exposure protected against morphological changes to the epithelial and connective tissue compartments of HSE. Pistachio antioxidants preserved overall skin thickness and organization, as well as fibroblast morphology, in HSE exposed to UVA irradiation. However, this protection was not substantiated by the analysis of the proliferation of keratinocytes and apoptosis of fibroblasts. Additional studies are warranted to elucidate the basis of these discordant results and extend research into the potential role of pistachio bioactives promoting skin health.

Inhibition of phorbol ester-induced tumor promotion in mice by vitamin A analog and anti-inflammatory steroid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weeks, C.E.; Slaga, T.J.; Hennings, H.

1979-08-01

The effects of a vitamin A analog, TMMP ethyl retinoate (abbreviated Ro 10-9359), and an anti-inflammatory steroid, fluocinoione acetonide (abbreviated FA), given alone or together were studied in a two-stage carcinogenesis system. the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used as the tumor promoter in a DMBA-initiated mouse skin system. Two stocks of female mice, which differ in their degrees of sensitivity to skin carcinogenesis, were used. A dose-dependent inhibition of carcinogenic expression, as determined by a decreased number of papillomas per animal, was observed in each mouse stock with the use of both FA and Ro 10-9359 were given alone.more » When FA and RO 10-9359 were given together, an enhanced effect on the lowering of tumor incidence was noted. FA effectively inhibited tumor formation in the sensitive mouse stock even when the steroid was given 1 day prior to TPA treatment under conditions of unusually high doses of initiator (DMBA) and/or promoter (TPA). These results suggest that both anti-inflammatory steroids and retinoids inhibit tumor promotion and can be effectively used as a combination regimen for increased chemopreventive response.« less

Impact assessment of energy-efficient lighting in patients with lupus erythematosus: a pilot study.

PubMed

Fenton, L; Dawe, R; Ibbotson, S; Ferguson, J; Silburn, S; Moseley, H

2014-03-01

Patients with lupus erythematosus (LE) are often abnormally photosensitive. Ultraviolet (UV) exposure can not only induce cutaneous lesions but may also contribute to systemic flares and disease progression. Various forms of energy-efficient lighting have been shown to emit UV radiation. To determine the effects of these emissions on individuals with LE. This assessment investigated cutaneous responses to repeated exposures from three types of lighting: compact fluorescent lamp (CFL), light-emitting diode (LED) and energy-efficient halogen (EEH). The subjects were 15 patients with LE and a control group of five healthy volunteers. No cutaneous LE lesions were induced by any of the light sources. Delayed skin erythema was induced at the site of CFL irradiation in six of the 15 patients with LE and two of the five healthy subjects. Erythema was increased in severity and more persistent in patients with LE. One patient with LE produced a positive delayed erythema to the EEH. A single patient with LE produced immediate abnormal erythemal responses to the CFL, LED and EEH. Further investigation revealed that this patient also had solar urticaria. All other subjects had negative responses to LED exposure. Compact fluorescent lamps emit UV that can induce skin erythema in both individuals with LE and healthy individuals when situated in close proximity. However, this occurs to a greater extent and is more persistent in patients with LE. EEHs emit UVA that can induce erythema in patients with LE. LEDs provide a safer alternative light source without risk of UV exposure. © 2013 British Association of Dermatologists.

Solar-simulating irradiation of the skin of human subjects in vivo produces Langerhans cell responses distinct from irradiation ex vivo and in vitro.

PubMed

Laihia, J K; Jansen, C T

2000-08-01

It has been postulated that Langerhans cells (LC) provide tolerogenic signals in the local impairment of cutaneous immune functions and antigen-specific tolerance induced by UV radiation. Studies in vitro and ex vivo have indicated that UV radiation may down-regulate the expression of costimulatory molecules on LC, leading to reduced antigen-presenting function. In contrast, we recently observed an up-regulatory stage in the number of human epidermal LC with induced expression of B7 costimulatory molecules 12-24 h after solar-simulating UV radiation (SSR) in vivo. To examine the apparent discrepancy between the observed human LC responses in vitro, ex vivo and in vivo, we compared the three protocols in a parallel fashion. The intact skin as well as skin explants and epidermal cell suspensions from the same individuals were irradiated with a single erythematogenic dose of SSR. The expression of cell surface markers in the epidermal cells was analysed with flow cytometry 24 h later. The number of CD1a+/HLA-DR+ LC increased post-SSR in vivo by a factor of 2.8+/-0.4, whereas in irradiated skin explants ex vivo or in cell suspensions in vitro, reduced numbers were seen. HLA-DR expression intensities were found to have increased on DR+ and CD1a+/DR+ cells in vivo. Similarly, SSR induced B7-2 (CD86) expression in CD1a+ cells significantly in vivo (P=0.031) but reduced the expression ex vivo or in vitro. We conclude that the early up-regulatory stage of human LC number and membrane markers, recorded at 24 h after a single exposure to SSR, is exclusively an in vivo phenomenon.

Actinic keratosis among seafarers.

PubMed

Oldenburg, M; Kuechmeister, B; Ohnemus, U; Baur, X; Moll, I

2013-11-01

The aim of this study was to assess the prevalence of UV-induced actinic keratosis and further skin lesions. A newly developed questionnaire about lifetime UV radiation exposure was completed by 514 seafarers. An experienced dermatologist inspected the whole-body skin status of all participants. The questionnaire revealed a pre-employment UV radiation exposure in 104 seafarers, sunbed use in 26 subjects and a median work-related UV radiation exposure at sea of 20 years. The diagnosis of actinic keratoses was made in 94 seafarers and the clinical diagnosis of skin cancers in 48 seafarers (28 basal cell carcinoma, 11 squamous cell carcinoma, 9 malignant melanoma). After age standardisation according to a European reference population, the male European seafarers in this study had a 1.80-fold increased risk of actinic keratosis. Actinic keratoses [OR 1.03 (1.01-1.05)] and squamous cell carcinoma [OR 1.07 (1.01-1.13)] were related to the duration of seafaring time in years. A significant association was also found between actinic keratosis/squamous cell carcinoma and sunlight exposure during home leave [OR 1.67 (1.03-2.81) and OR 6.19 (1.18-32.40)]. Furthermore, the engine room personnel-especially the technical officers-were at higher risk of developing actinic keratosis. Due to the high prevalence of actinic keratosis especially among older seafarers with fair skin, with longer duration of seafaring employment at sea and with higher UV exposure during home leave, more intensive advice should be given on sun protection both at sea and ashore.

Natural Substances for Prevention of Skin Photoaging: Screening Systems in the Development of Sunscreen and Rejuvenation Cosmetics.

PubMed

Kostyuk, Vladimir; Potapovich, Alla; Albuhaydar, Ahmed R; Mayer, Wolfgang; De Luca, Chiara; Korkina, Liudmila

2018-04-01

Solar broadband UV irradiation is commonly regarded as a major causative reason for cutaneous photoaging. The pro-aging molecular pathways and cellular targets affected by UVA+UVB light in human skin have been extensively investigated. Notwithstanding growing knowledge in mechanisms of photoaging, research and development of clinically efficient, nontoxic, and sustainable topical preparations providing full physical, chemical, and biological photoprotection still remain a great challenge for pharmaceutical and cosmetic industries. In this study, we are proposing a panel of the in vitro methods for preselection of natural photoprotective substances with high photostability and low phototoxicity able of absorbing a broadband UVA+UVB irradiation (physical sunscreen), reducing UV-related overproduction of free radicals and loss of endogenous antioxidants (chemical protection), and attenuating UV-induced cytotoxicity and immune and metabolic responses (biological protection) in primary human epidermal keratinocytes and immortalized human keratinocyte cultures. Our data showed that secondary metabolites biosynthesized in plant cells in response to UV irradiation, such as phenylpropanoids and their glycosylated metabolites, aglycons and glycosylated flavonoids, and leontopodic acids, hold the best promise for complete natural topical prevention of photoaging and rejuvenation of photoaged skin. Meristem plant cell cultures elicited by solar simulating UV could be the most environmentally sustainable biotechnological source of polyphenols with combined photoprotective and antiaging properties.

Natural Substances for Prevention of Skin Photoaging: Screening Systems in the Development of Sunscreen and Rejuvenation Cosmetics

PubMed Central

Kostyuk, Vladimir; Potapovich, Alla; Albuhaydar, Ahmed R.; Mayer, Wolfgang; De Luca, Chiara

2018-01-01

Abstract Solar broadband UV irradiation is commonly regarded as a major causative reason for cutaneous photoaging. The pro-aging molecular pathways and cellular targets affected by UVA+UVB light in human skin have been extensively investigated. Notwithstanding growing knowledge in mechanisms of photoaging, research and development of clinically efficient, nontoxic, and sustainable topical preparations providing full physical, chemical, and biological photoprotection still remain a great challenge for pharmaceutical and cosmetic industries. In this study, we are proposing a panel of the in vitro methods for preselection of natural photoprotective substances with high photostability and low phototoxicity able of absorbing a broadband UVA+UVB irradiation (physical sunscreen), reducing UV-related overproduction of free radicals and loss of endogenous antioxidants (chemical protection), and attenuating UV-induced cytotoxicity and immune and metabolic responses (biological protection) in primary human epidermal keratinocytes and immortalized human keratinocyte cultures. Our data showed that secondary metabolites biosynthesized in plant cells in response to UV irradiation, such as phenylpropanoids and their glycosylated metabolites, aglycons and glycosylated flavonoids, and leontopodic acids, hold the best promise for complete natural topical prevention of photoaging and rejuvenation of photoaged skin. Meristem plant cell cultures elicited by solar simulating UV could be the most environmentally sustainable biotechnological source of polyphenols with combined photoprotective and antiaging properties. PMID:28661208

Might outdoor heat stress be considered a proxy for the unperceivable effect of the ultraviolet-induced risk of erythema in Florence?

PubMed

Morabito, Marco; Grifoni, Daniele; Crisci, Alfonso; Fibbi, Luca; Orlandini, Simone; Gensini, Gian Franco; Zipoli, Gaetano

2014-01-05

Erythema is the most familiar short-term symptom of human skin associated with overexposure to unperceivable ultraviolet radiation (UV). However, people are able to perceive the warm infrared component of the solar radiation by means of thermal (dis)comfort. This study investigated the potentiality of perceived outdoor heat stress as a valuable proxy for the unperceivable effect of UV-induced risk of erythema in a Mediterranean city. Meteorological data and UVB (280-320nm) measurements were obtained for the 2004-2012 period by a weather station located in the municipality of Florence. Continuous measurements of erythemally effective UV (UVEry) were performed by means of a broadband temperature-corrected radiometer with the spectral response close to the erythemal action spectrum. Hourly UVEry doses were expressed as Standard Erythemal Doses (SEDs). The newly developed Universal Thermal Climate Index (UTCI), that represents the state-of-the-art of outdoor thermal (dis)comfort evaluation, was also assessed. Descriptive analyses of the hourly distribution per month of the frequencies of days with heat stress and UVEry exceeding 2.0, 3.0, 4.5 and 6.0 SEDs were carried out based on the general skin-type characteristics. The association between UVEry and UTCI was analyzed by a two-way contingency table approach. The probability of UVEry exceeding specific SED thresholds when heat stress occurs was often significantly higher than the same probability when no heat stress is perceived. Furthermore, increased magnitudes of the ratios, ranging from the very sensitive to the minimally sensitive skin types, were also found. However, during several months, too many days occur without any signs of heat discomfort, even when people may be exposed to relevant doses of harmful UVEry for the skin of various phototypes. These findings underlie the need for public health authorities to provide differentiated advice per month in relation to potential UV skin damage in the city of Florence. Copyright © 2013 Elsevier B.V. All rights reserved.

Skin cancers in elderly patients.

PubMed

Malaguarnera, Giulia; Giordano, Maria; Cappellani, Alessandro; Berretta, Massimiliano; Malaguarnera, Michele; Perrotta, Rosario Emanuele

2013-11-01

Cancer in older people is a common problem worldwide. Among various types of cancer, skin cancers represent an important percentage. The principal risk factors are sun exposure, family history of skin cancer, fair skin color, but also the age plays an important role in the genesis of skin cancers. In older people there are a more prolonged exposure to carcinogenesis and a decreased functionality of reparation mechanisms of the cells so they acquire a selective advantage of growing and proliferating. At the same time age causes alteration in immune system by increasing NK-cells absolute number and decreasing both the endogenous and the lymphokine-induced lytic activities. The anti-tumor immune response is also mediated by the cytotoxic T- lymphocytes and in the elderly a strong reduction of T-cell function has been demonstrated. In elderly patients the diagnosis and the treatment of skin cancers can be different from younger counterpart. For example in older patients with melanoma is important to evaluate Breslow depth while higher mitotic rate has major value in younger patients. Moreover, the treatment should consider the performance status of patients and their compliance.

STUDIES ON RADIATION-INDUCED TANNING OF SKIN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quevedo, W.C. Jr.; Smith, J.A.

1963-02-15

After repeated exposure to uv, hyperpigmentation developed in the general body skin of hairless mice and in the plantar skin of mice of a number of strains selected on the basis of characteristic differences in coat coloration. The hyperpigmentation was due largely to an increase in melanin synthesis by epidermal melanocytes. The major coat color genes had a profound effect on this process by having an influence on melanocyte distribution and, possibly, proliferation; the numbers of melanocytes activated by uv radiation; the amount of pigment synthesized by melanocytes, either retained by them or transferred to epidermal cells; the color andmore » size of pigment granules elaborated by melandocytes; and the shape of the melanocytes. Possible mechanisms involved in the response of epidermal melanocytes to radiations are discussed. (auth)« less

Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta.

PubMed

Nicolay, Nils H; Carter, Rebecca; Hatch, Stephanie B; Schultz, Niklas; Prevo, Remko; McKenna, W Gillies; Helleday, Thomas; Sharma, Ricky A

2012-11-01

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.

Six week evaluation of the potential for topical desoximetasone 0.25% spray to induce photoallergic skin reaction.

PubMed

Patel, Nupur U; Gowda, Asha; Grammenos, Alexandra; Onikoyi, Omobola; Feldman, Steven R

2018-05-01

Desoximetasone 0.25% topical spray is a novel formulation that has not been tested or approved for safety and efficacy. The primary objective was to determine the potential of desoximetasone 0.25 and 0.05% topical sprays, as well as a vehicle to induce photoallergic skin reaction after repeated topical application and irradiation to the skin using a controlled photopatch testing procedure. 53 subjects completed the study, each with six application sites (two of each treatment), three of which were irradiated and three non-irradiated, for an induction period of three weeks and then challenge period at week 6. Desoximetasone 0.25 and 0.05%, as well as vehicle showed no evidence of potential to induce photosensitization. There was statistically significantly greater irritation at the vehicle irradiated site in comparison to the irradiated treatment area of desoximetasone 0.25% (p = .005) and the irradiated treatment area of desoximetasone 0.05% (p = .008). Our results suggest that regular treatment with desoximetasone 0.25 and 0.05% spray, followed by UV light exposure does not induce photosensitization or photo-irritation. These findings increase confidence for the use of this topical spray in eczema or psoriasis patients who may also be receiving UV light therapy and may contribute to the clinical management of these patients.

In-vivo characterization of endogenous porphyrin fluorescence from DMBA-treated Swiss Albino mice skin carcinogenesis for measuring tissue transformation

NASA Astrophysics Data System (ADS)

Ganesan, Singaravelu; Ebenezar, Jeyasingh; Hemamalini, Srinivasan; Aruna, Prakasa R.

2002-05-01

Steady state fluorescence spectroscopic characterization of endogenous porphyrin emission from DMBA treated skin carcinogenesis in Swiss albino mice was carried out. The emission of endogenous porphyrin from normal and abnormal skin tissues was studied both in the presence and absence of exogenous ALA to compare the resultant porphyrin emission characterictics. The mice skin is excited at 405nm and emission spectra are scanned from 430 to 700nm. The average fluorescence emission spectra of mice skin at normal and various tissues transformation conditions were found to be different. Two peaks around 460nm and 636nm were observed and they may be attributed to NADH, Elastin and collagen combination and endogenous porphyrin emission. The intensity at 636nm increases as the stage of the cancer increases. Although exogenous ALA enhances the PPIX level in tumor, the synthesis of PPIX was also found in normal surrounding skin, in fact, with higher concentration than that of tumor tissues.

Final report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmetics.

PubMed

Elmore, Amy R

2005-01-01

L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate function in cosmetic formulations primarily as antioxidants. Ascorbic Acid is commonly called Vitamin C. Ascorbic Acid is used as an antioxidant and pH adjuster in a large variety of cosmetic formulations, over 3/4 of which were hair dyes and colors at concentrations between 0.3% and 0.6%. For other uses, the reported concentrations were either very low (<0.01%) or in the 5% to 10% range. Calcium Ascorbate and Magnesium Ascorbate are described as antioxidants and skin conditioning agents--miscellaneous for use in cosmetics, but are not currently used. Sodium Ascorbyl Phosphate functions as an antioxidant in cosmetic products and is used at concentrations ranging from 0.01% to 3%. Magnesium Ascorbyl Phosphate functions as an antioxidant in cosmetics and was reported being used at concentrations from 0.001% to 3%. Sodium Ascorbate also functions as an antioxidant in cosmetics at concentrations from 0.0003% to 0.3%. Related ingredients (Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate) have been previously reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel and found "to be safe for use as cosmetic ingredients in the present practices of good use." Ascorbic Acid is a generally recognized as safe (GRAS) substance for use as a chemical preservative in foods and as a nutrient and/or dietary supplement. Calcium Ascorbate and Sodium Ascorbate are listed as GRAS substances for use as chemical preservatives. L-Ascorbic Acid is readily and reversibly oxidized to L-dehydroascorbic acid and both forms exist in equilibrium in the body. Permeation rates of Ascorbic Acid through whole and stripped mouse skin were 3.43 +/- 0.74 microg/cm(2)/h and 33.2 +/- 5.2 microg/cm(2)/h. Acute oral and parenteral studies in mice, rats, rabbits, guinea pigs, dogs, and cats demonstrated little toxicity. Ascorbic Acid and Sodium Ascorbate acted as a nitrosation inhibitor in several food and cosmetic product studies. No compound-related clinical signs or gross or microscopic pathological effects were observed in either mice, rats, or guinea pigs in short-term studies. Male guinea pigs fed a control basal diet and given up to 250 mg Ascorbic Acid orally for 20 weeks had similar hemoglobin, blood glucose, serum iron, liver iron, and liver glycogen levels compared to control values. Male and female F344/N rats and B6C3F(1) mice were fed diets containing up to 100,000 ppm Ascorbic Acid for 13 weeks with little toxicity. Chronic Ascorbic Acid feeding studies showed toxic effects at dosages above 25 mg/kg body weight (bw) in rats and guinea pigs. Groups of male and female rats given daily doses up to 2000 mg/kg bw Ascorbic Acid for 2 years had no macro- or microscopically detectable toxic lesions. Mice given Ascorbic Acid subcutaneous and intravenous daily doses (500 to 1000 mg/kg bw) for 7 days had no changes in appetite, weight gain, and general behavior; and histological examination of various organs showed no changes. Ascorbic Acid was a photoprotectant when applied to mice and pig skin before exposure to ultraviolet (UV) radiation. The inhibition of UV-induced suppression of contact hypersensitivity was also noted. Magnesium Ascorbyl Phosphate administration immediately after exposure in hairless mice significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to UV radiation. Pregnant mice and rats were given daily oral doses of Ascorbic Acid up to 1000 mg/kg bw with no indications of adult-toxic, teratogenic, or fetotoxic effects. Ascorbic Acid and Sodium Ascorbate were not genotoxic in several bacterial and mammalian test systems, consistent with the antioxidant properties of these chemicals. In the presence of certain enzyme systems or metal ions, evidence of genotoxicity was seen. The National Toxicology Program (NTP) conducted a 2-year oral carcinogenesis bioassay of Ascorbic Acid (25,000 and 50,000 ppm) in F344/N rats and B6C3F(1) mice. Ascorbic Acid was not carcinogenic in either sex of both rats and mice. Inhibition of carcinogenesis and tumor growth related to Ascorbic Acid's antioxidant properties has been reported. Sodium Ascorbate has been shown to promote the development of urinary carcinomas in two-stage carcinogenesis studies. Dermal application of Ascorbic Acid to patients with radiation dermatitis and burn victims had no adverse effects. Ascorbic Acid was a photoprotectant in clinical human UV studies at doses well above the minimal erythema dose (MED). An opaque cream containing 5% Ascorbic Acid did not induce dermal sensitization in 103 human subjects. A product containing 10% Ascorbic Acid was nonirritant in a 4-day minicumulative patch assay on human skin and a facial treatment containing 10% Ascorbic Acid was not a contact sensitizer in a maximization assay on 26 humans. Because of the structural and functional similarities of these ingredients, the Panel believes that the data on one ingredient can be extrapolated to all of them. The Expert Panel attributed the finding that Ascorbic Acid was genotoxic in these few assay systems due to the presence of other chemicals, e.g., metals, or certain enzyme systems, which effectively convert Ascorbic Acid's antioxidant action to that of a pro-oxidant. When Ascorbic Acid acts as an antioxidant, the Panel concluded that Ascorbic Acid is not genotoxic. Supporting this view were the carcinogenicity studies conducted by the NTP, which demonstrated no evidence of carcinogenicity. Ascorbic Acid was found to effectively inhibit nitrosamine yield in several test systems. The Panel did review studies in which Sodium Ascorbate acted as a tumor promoter in animals. These results were considered to be related to the concentration of sodium ions and the pH of urine in the test animals. Similar effects were seen with sodium bicarbonate. Because of the concern that certain metal ions may combine with these ingredients to produce pro-oxidant activity, the Panel cautioned formulators to be certain that these ingredients are acting as antioxidants in cosmetic formulations. The Panel believed that the clinical experience in which Ascorbic Acid was used on damaged skin with no adverse effects and the repeat-insult patch test (RIPT) using 5% Ascorbic Acid with negative results supports the finding that this group of ingredients does not present a risk of skin sensitization. These data coupled with an absence of reports in the clinical literature of Ascorbic Acid sensitization strongly support the safety of these ingredients.

Ethanol extract of Dalbergia odorifera protects skin keratinocytes against ultraviolet B-induced photoaging by suppressing production of reactive oxygen species.

PubMed

Ham, Sun Ah; Hwang, Jung Seok; Kang, Eun Sil; Yoo, Taesik; Lim, Hyun Ho; Lee, Won Jin; Paek, Kyung Shin; Seo, Han Geuk

2015-01-01

Dalbergia odorifera T. Chen (Leguminosae), an indigenous medicinal herb, has been widely used in northern and eastern Asia to treat diverse diseases. Here, we investigated the anti-senescent effects of ethanolic extracts of Dalbergia odorifera (EEDO) in ultraviolet (UV) B-irradiated skin cells. EEDO significantly inhibited UVB-induced senescence of human keratinocytes in a concentration-dependent manner, concomitant with inhibition of reactive oxygen species (ROS) generation. UVB-induced increases in the levels of p53 and p21, biomarkers of cellular senescence, were almost completely abolished in the presence of EEDO. Sativanone, a major constituent of EEDO, also attenuated UVB-induced senescence and ROS generation in keratinocytes, indicating that sativanone is an indexing (marker) molecule for the anti-senescence properties of EEDO. Finally, treatment of EEDO to mice exposed to UVB significantly reduced ROS levels and the number of senescent cells in the skin. Thus, EEDO confers resistance to UVB-induced cellular senescence by inhibiting ROS generation in skin cells.

8-Oxo-2'-deoxyguanosine ameliorates UVB-induced skin damage in hairless mice by scavenging reactive oxygen species and inhibiting MMP expression.

PubMed

Lee, Jin-Ku; Ko, Seong-Hee; Ye, Sang-Kyu; Chung, Myung-Hee

2013-04-01

Skin is uniquely vulnerable to damage caused by reactive oxygen species (ROS), which are most commonly produced in response to ultraviolet (UV) light. ROS generated at injury sites play an important role in modulating the inflammatory response. Besides inhibiting Rac, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxo-dG) has also shown notable antioxidant action. We tested whether 8-oxo-dG could protect skin from UVB-induced damage by scavenging ROS. HaCaT cells and hairless mice were irradiated with 15 and 180 mJ/cm(2) narrow-spectrum UVB, respectively. ROS generation was detected through incubation with DCFDA and confocal microscopy. Western blot analyses and immunohistochemistry were performed to verify the activities of ERK, JNK, p38, ATF-2, and c-Jun, and the expression of matrix metalloproteinases (MMPs), in UVB-irradiated HaCaT cells and murine skin. Hydrogen peroxide production and protein carbonyl concentrations were measured in UVB-damaged mouse skin. MMP-1 and MMP-9 expression in UVB-irradiated HaCaT cells was measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In UVB-irradiated HaCaT cells, 8-oxo-dG inhibited ROS production, subsequent activation of mitogen-activated protein kinase (MAPK), ATF-2, and c-Jun, and MMP expression. It also prevented UV-induced skin reactions in hairless mice, inhibiting the increase in protein carbonyl content, activation of MAPKs, ATF-2, and c-Jun, the increases in MMP-9 and -13 expression, and epidermal hyperplasia. 8-oxo-dG can be considered an endogenous antioxidant and its potent antioxidant activity might be a beneficial property that could be exploited to protect skin from ROS-associated photodamage. Copyright © 2013. Published by Elsevier Ireland Ltd.

Fibroblasts from patients with hereditary cutaneous malignant melanoma are abnormally sensitive to the mutagenic effect of simulated sunlight and 4-nitroquinoline 1-oxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Howell, J.N.; Greene, M.H.; Corner, R.C.

Because of a possible etiologic link between mutations and carcinogenesis, the authors compared fibroblasts derived from skin biopsies of several patients with hereditary cutaneous malignant melanoma and the dysplastic nevus syndrome for sensitivity to the mutagenic and/or cytotoxic effect of broad-spectrum simulated sunlight and of a UV mimetic carcinogen, 4-nitroquinoline 1-oxide (4NQO). The genetic marker was resistant to 6-thioguanine; loss of colony-forming ability was the assay for cytotoxicity. All five strains tested were more sensitive than normal to the killing effect of 4NQO (slopes of survival curves were 2- to 3-fold steeper), but only one strain was hypersensitive to killingmore » by Sun Lamp radiation. Two strains were tested for mutagenicity. The response of each to the mutagenic action of these agents corresponded to its response to cell killing. Both strains were hypermutable after exposure to 4NQO, but only one showed a higher than normal frequency of mutants induced by simulated sunlight. The finding that nonmalignant fibroblasts from patients with a hereditary variant of malignant fibroblasts from patients with a hereditary variant of malignant melanoma are abnormally susceptible to carcinogen-induced mutations suggests that hypersensitivity to mutagens contributes to risk of melanoma in patients. It also supports the somatic cell mutation hypothesis for the origin of cancer. 46 references, 3 figures.« less

207-nm UV light - a promising tool for safe low-cost reduction of surgical site infections. I: in vitro studies.

PubMed

Buonanno, Manuela; Randers-Pehrson, Gerhard; Bigelow, Alan W; Trivedi, Sheetal; Lowy, Franklin D; Spotnitz, Henry M; Hammer, Scott M; Brenner, David J

2013-01-01

0.5% to 10% of clean surgeries result in surgical-site infections, and attempts to reduce this rate have had limited success. Germicidal UV lamps, with a broad wavelength spectrum from 200 to 400 nm are an effective bactericidal option against drug-resistant and drug-sensitive bacteria, but represent a health hazard to patient and staff. By contrast, because of its limited penetration, ~200 nm far-UVC light is predicted to be effective in killing bacteria, but without the human health hazards to skin and eyes associated with conventional germicidal UV exposure. The aim of this work was to test the biophysically-based hypothesis that ~200 nm UV light is significantly cytotoxic to bacteria, but minimally cytotoxic or mutagenic to human cells either isolated or within tissues. A Kr-Br excimer lamp was used, which produces 207-nm UV light, with a filter to remove higher-wavelength components. Comparisons were made with results from a conventional broad spectrum 254-nm UV germicidal lamp. First, cell inactivation vs. UV fluence data were generated for methicillin-resistant S. aureus (MRSA) bacteria and also for normal human fibroblasts. Second, yields of the main UV-associated pre-mutagenic DNA lesions (cyclobutane pyrimidine dimers and 6-4 photoproducts) were measured, for both UV radiations incident on 3-D human skin tissue. We found that 207-nm UV light kills MRSA efficiently but, unlike conventional germicidal UV lamps, produces little cell killing in human cells. In a 3-D human skin model, 207-nm UV light produced almost no pre-mutagenic UV-associated DNA lesions, in contrast to significant yields induced by a conventional germicidal UV lamp. As predicted based on biophysical considerations, 207-nm light kills bacteria efficiently but does not appear to be significantly cytotoxic or mutagenic to human cells. Used appropriately, 207-nm light may have the potential for safely and inexpensively reducing surgical-site infection rates, including those of drug-resistant origin.

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

PubMed

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.

CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation.

PubMed

Chang, Chung-Hsing; Kuo, Che-Jung; Ito, Takamichi; Su, Yu-Ya; Jiang, Si-Tse; Chiu, Min-Hsi; Lin, Yi-Hsiung; Nist, Andrea; Mernberger, Marco; Stiewe, Thorsten; Ito, Shosuke; Wakamatsu, Kazumasa; Hsueh, Yi-An; Shieh, Sheau-Yann; Snir-Alkalay, Irit; Ben-Neriah, Yinon

2017-09-19

Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by Csnk1a1 ) in skin physiology, we crossed mice harboring floxed Csnk1a1 with mice expressing K14-Cre-ER T2 to generate mice in which tamoxifen induces the deletion of Csnk1a1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after Csnk1a1 ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14-Cre-ER T2 CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte-stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn.

CK1α ablation in keratinocytes induces p53-dependent, sunburn-protective skin hyperpigmentation

PubMed Central

Chang, Chung-Hsing; Kuo, Che-Jung; Ito, Takamichi; Su, Yu-Ya; Jiang, Si-Tse; Chiu, Min-Hsi; Lin, Yi-Hsiung; Nist, Andrea; Mernberger, Marco; Stiewe, Thorsten; Ito, Shosuke; Wakamatsu, Kazumasa; Hsueh, Yi-An; Shieh, Sheau-Yann; Snir-Alkalay, Irit; Ben-Neriah, Yinon

2017-01-01

Casein kinase 1α (CK1α), a component of the β-catenin destruction complex, is a critical regulator of Wnt signaling; its ablation induces both Wnt and p53 activation. To characterize the role of CK1α (encoded by Csnk1a1) in skin physiology, we crossed mice harboring floxed Csnk1a1 with mice expressing K14–Cre–ERT2 to generate mice in which tamoxifen induces the deletion of Csnk1a1 exclusively in keratinocytes [single-knockout (SKO) mice]. As expected, CK1α loss was accompanied by β-catenin and p53 stabilization, with the preferential induction of p53 target genes, but phenotypically most striking was hyperpigmentation of the skin, importantly without tumorigenesis, for at least 9 mo after Csnk1a1 ablation. The number of epidermal melanocytes and eumelanin levels were dramatically increased in SKO mice. To clarify the putative role of p53 in epidermal hyperpigmentation, we established K14–Cre–ERT2 CK1α/p53 double-knockout (DKO) mice and found that coablation failed to induce epidermal hyperpigmentation, demonstrating that it was p53-dependent. Transcriptome analysis of the epidermis revealed p53-dependent up-regulation of Kit ligand (KitL). SKO mice treated with ACK2 (a Kit-neutralizing antibody) or imatinib (a Kit inhibitor) abrogated the CK1α ablation-induced hyperpigmentation, demonstrating that it requires the KitL/Kit pathway. Pro-opiomelanocortin (POMC), a precursor of α-melanocyte–stimulating hormone (α-MSH), was not activated in the CK1α ablation-induced hyperpigmentation, which is in contrast to the mechanism of p53-dependent UV tanning. Nevertheless, acute sunburn effects were successfully prevented in the hyperpigmented skin of SKO mice. CK1α inhibition induces skin-protective eumelanin but no carcinogenic pheomelanin and may therefore constitute an effective strategy for safely increasing eumelanin via UV-independent pathways, protecting against acute sunburn. PMID:28878021

INDUCTION OF SKIN PAPILLOMAS IN THE SENCAR MOUSE AS A TIER 2 CARCINOGENESIS BIOASSAY

EPA Science Inventory

The Toxic Substances Control Act mandates the testing of industrial chemicals for which insufficient evidence of safety exists. One of the more critical areas in chemical carcinogenesis testing is a dependable approach to confirmatory tests (tier 2) of identified positives at a s...

Pigmentation after single and multiple UV-exposures depending on UV-spectrum.

PubMed

Ravnbak, M H; Wulf, H C

2007-04-01

Minimal pigmentation dose (MMD) after a single UV-exposure is well investigated. Whereas only few studies have established MMD after multiple UV-exposures and mainly in fair-skinned persons. The purpose of this study was to establish MMD 1 week after, respectively, one and five UV-exposures in volunteers with a large variation in constitutive pigmentation. A total of 52 volunteers (skin Types II-V) had skin pigmentation quantified by reflectance spectroscopy. They were UV-exposed on the back for 1 and 5 days using a Solar Simulator, narrowband UVB, broadband UVA and UVA1. For all sources a higher dose was needed the more pigmented the skin, except for UVA1. After one UV-exposure, we found a significant positive linear correlation between UV-dose to one MMD, skin type and pre-exposure skin pigmentation. After five UV-exposures the positive linear correlation between UV-dose and MMD and skin type was only significant for narrow band UVB, pre-exposure skin pigmentation was significant also for Solar Simulator. For UVA and particularly UVA1 the MMD was independent of pre-exposure pigmentation. The number of SED to MMD is therefore almost the same for very fair-skinned and dark-skinned persons. Pre-exposure pigmentation was clearly more predictive of MMD than skin type. 50% of MMD equals a pigmentation increase of 1%. The shorter the wavelengths the higher the SED to produce MMD. Solar was the least melanogenic and UVA1 the most melanogenic. For the UVB-sources a higher dose was needed the more pigmented the skin. For UVA the MMD was independent of pre-exposure pigmentation.

Far-infrared suppresses skin photoaging in ultraviolet B-exposed fibroblasts and hairless mice.

PubMed

Chiu, Hui-Wen; Chen, Cheng-Hsien; Chen, Yi-Jie; Hsu, Yung-Ho

2017-01-01

Ultraviolet (UV) induces skin photoaging, which is characterized by thickening, wrinkling, pigmentation, and dryness. Collagen, which is one of the main building blocks of human skin, is regulated by collagen synthesis and collagen breakdown. Autophagy was found to block the epidermal hyperproliferative response to UVB and may play a crucial role in preventing skin photoaging. In the present study, we investigated whether far-infrared (FIR) therapy can inhibit skin photoaging via UVB irradiation in NIH 3T3 mouse embryonic fibroblasts and SKH-1 hairless mice. We found that FIR treatment significantly increased procollagen type I through the induction of the TGF-β/Smad axis. Furthermore, UVB significantly enhanced the expression of matrix metalloproteinase-1 (MMP-1) and MMP-9. FIR inhibited UVB-induced MMP-1 and MMP-9. Treatment with FIR reversed UVB-decreased type I collagen. In addition, FIR induced autophagy by inhibiting the Akt/mTOR signaling pathway. In UVB-induced skin photoaging in a hairless mouse model, FIR treatment resulted in decreased skin thickness in UVB irradiated mice and inhibited the degradation of collagen fibers. Moreover, FIR can increase procollagen type I via the inhibition of MMP-9 and induction of TGF-β in skin tissues. Therefore, our study provides evidence for the beneficial effects of FIR exposure in a model of skin photoaging.

CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure.

PubMed

Huang, S; Guo, S; Guo, F; Yang, Q; Xiao, X; Murata, M; Ohnishi, S; Kawanishi, S; Ma, N

2013-01-14

Inorganic arsenic is a well-known human skin carcinogen. Chronic arsenic exposure results in various types of human skin lesions, including squamous cell carcinoma (SCC). To investigate whether mutant stem cells participate in arsenic-associated carcinogenesis, we repeatedly exposed the HaCaT cells line to an environmentally relevant level of arsenic (0.05 ppm) in vitro for 18 weeks. Following sodium arsenic arsenite administration, cell cycle, colony-forming efficiency (CFE), cell tumorigenicity, and expression of CD44v6, NF-κB and p53, were analyzed at different time points (0, 5, 10, 15, 20, 25 and 30 passages). We found that a chronic exposure of HaCaT cells to a low level of arsenic induced a cancer stem- like phenotype. Furthermore, arsenic-treated HaCaT cells also became tumorigenic in nude mice, their growth cycle was predominantly in G2/M and S phases. Relative to nontreated cells, they exhibited a higher growth rate and a significant increase in CFE. Western blot analysis found that arsenic was capable of increasing cell proliferation and sprouting of cancer stem-like phenotype. Additionally, immunohistochemical analysis demonstrated that CD44v6 expression was up-regulated in HaCaT cells exposed to a low level of arsenic during early stages of induction. The expression of CD44v6 in arsenic-treated cells was positively correlated with their cloning efficiency in soft agar (r=0.949, P=0.01). Likewise, the expressions of activating transcription factor NF-κB and p53 genes in the arsenic-treated HaCaT cells were significantly higher than that in non-treated cells. Higher expressions of CD44v6, NF-κB and p53 were also observed in tumor tissues isolated from Balb/c nude mice. The present results suggest that CD44v6 may be a biomarker of arsenic-induced neoplastic transformation in human skin cells, and that arsenic promotes malignant transformation in human skin lesions through a NF-κB signaling pathway-stimulated expression of CD44v6.

Preventive effects of β-thujaplicin against UVB-induced MMP-1 and MMP-3 mRNA expressions in skin fibroblasts.

PubMed

Cherng, Jong Yuh; Chen, Li Yin; Shih, Mei Fen

2012-01-01

Solar UV radiation damages human skin by affecting skin tone and resiliency and leads to premature aging (photoaging). The skin damage is caused by the activation of the AP-1 transcription factor, which increases matrix metalloproteinase (MMP) expression and collagen degradation. An increase of interleukin (IL)-6 is also correlated with the activation of MMP-1 expression. β-thujaplicin has shown both acaricidal and antimicrobial activities. Also, β-thujaplicin has been shown to be protective against apoptosis due to the oxidative effects of UV irradiation. However, the effect of β-thujaplicin on UVB-induced MMPs had not been investigated. In this study, after UVB exposure, MMP-1 and IL-6 production in human skin fibroblasts was examined in the presence of β-thujaplicin, vitamin C, and vitamin E. The expression of MMP-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP-1, TIMP-3) and procollagen mRNA was also investigated. Results showed that UVB-induced MMP-1 production was suppressed by the β-thujaplicin treatment in a dose-dependent manner, but not by vitamin C and vitamin E. β-thujaplicin also prevented the up-regulation of MMP-1 and MMP-3 mRNA. Moreover, the UVB-suppressed procollagen gene expression was restored to normal by β-thujaplicin. Neither UVB nor β-thujaplicin affected the mRNA expression of TIMP-1 and TIMP-3. The IL-6 production induced by UVB was lower in β-thujaplicin treated fibroblasts than in the controls. In conclusion, this study shows the capability of β-thujaplicin in preventing MMP-1 production due to UVB irradiation via inhibition of MMP gene expression. Importantly, the UVB-suppressed procollagen gene expression can be restored to normal by β-thujaplicin. These findings indicate that β-thujaplicin is a promising and potent agent to inhibit UVB-induced MMP-1 and MMP-3 gene expression in skin fibroblasts.

Differential effects of topical vitamin E and C E Ferulic® treatments on ultraviolet light B-induced cutaneous tumor development in Skh-1 mice.

PubMed

Burns, Erin M; Tober, Kathleen L; Riggenbach, Judith A; Kusewitt, Donna F; Young, Gregory S; Oberyszyn, Tatiana M

2013-01-01

Because of the ever-increasing incidence of ultraviolet light B (UVB)-induced skin cancer, considerable attention is being paid to prevention through the use of both sunscreens and after sun treatments, many of which contain antioxidants. Vitamin E is included as an antioxidant in many sunscreens and lotions currently on the market. Studies examining the efficacy of vitamin E as a topical preventative agent for UVB-induced skin cancer have yielded conflicting results. A likely contributor to differences in study outcome is the stability of vitamin E in the particular formulation being tested. In the current study we examined the effects of topical vitamin E alone as well as vitamin E combined with vitamin C and ferulic acid in a more stable topical formula (C E Ferulic®). Mice were exposed to UVB for 10 weeks in order to induce skin damage. Then, before the appearance of any cutaneous lesions, mice were treated for 15 weeks with a topical antioxidant, without any further UVB exposure. We found that topical C E Ferulic decreased tumor number and tumor burden and prevented the development of malignant skin tumors in female mice with chronically UVB-damaged skin. In contrast, female mice chronically exposed to UVB and treated topically with vitamin E alone showed a trend towards increased tumor growth rate and exhibited increased levels of overall DNA damage, cutaneous proliferation, and angiogenesis compared to vehicle-treated mice. Thus, we have demonstrated that topical 5% alpha tocopherol may actually promote carcinogenesis when applied on chronically UVB-damaged skin while treating with a more stable antioxidant compound may offer therapeutic benefits.

Human papillomavirus types detected in skin warts and cancer differ in their transforming properties but commonly counteract UVB induced protective responses in human keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shterzer, Naama; Heyman, Dariya; Shapiro, Beny

In the present study, E6E7 and E6 proteins of human papillomaviruses (HPVs) associated with skin warts and cancer were compared for their transforming and carcinogenic abilities in primary human keratinocytes (PHKs). We show that E6E7 of cancer associated beta HPV types, notably 49 and 24, were able to extend the life span and enhance the clonogenic efficiency of PHKs when maintained in serum free/low calcium medium. Activities of the beta HPV E6E7 were lower than those of HPV16 E6E7. In contrast, E6 proteins from HPV types detected in skin warts or cancer, notably 10, 49 and 38, attenuated UVB inducedmore » protective responses in PHKs including cell death, proliferation arrest and accumulation of the proapoptotic proteins, p53, bax or bak. Together, this investigation revealed functional differences and commonalities between HPVs associated with skin warts and cancer, and allowed the identification of specific properties of beta HPVs supporting their involvement in skin carcinogenesis. - Highlights: • Primary keratinocytes were used to evaluate transforming and carcinogenic abilities of cutaneous HPVs. • E6E7 of cancer associated β HPV types transform primary human keratinocytes. • E6 proteins of cancer and wart associated HPVs inhibit UVB induced cell death. • E6s of cancer and wart associated HPVs attenuate UVB induced proliferation arrest. • E6s of cancer and wart associated HPVs attenuate UVB induced apoptosis signaling.« less

UVA-induced protection of skin through the induction of heme oxygenase-1.

PubMed

Xiang, Yuancai; Liu, Gang; Yang, Li; Zhong, Julia Li

2011-12-01

UVA (320-400 nm) and UVB (290-320 nm) are the major components of solar UV irradiation, which is associated with various pathological conditions. UVB causes direct damage to DNA of epidermal cells and is mainly responsible for erythema, immunosuppression, photoaging, and skin cancer. UVA has oxidizing properties that can cause damage or enhance UVB damaging effects on skin. On the other hand, UVA can also lead to high levels of heme oxygenase-1 (HO-1) expression of cells that can provide an antioxidant effect on skin as well as anti-inflammatory properties in mammals and rodents. Therefore, this review focuses on the potential protection of UVA wavebands for the skin immune response, instead of mechanisms that underlie UVA-induced damage. Also, the role of HO-1 in UVA-mediated protection against UVB-induced immunosuppression in skin will be summarized. Thus, this review facilitates further understanding of potential beneficial mechanisms of UVA irradiation, and using the longer UVA (UVA1, 340-400 nm) in combination with HO-1 for phototherapy and skin protection against sunlight exposure.

Influence of visible light on cutaneous hyperchromias: Clinical efficacy of broad-spectrum sunscreens.

PubMed

Martini, Ana Paula M; Maia Campos, Patricia M B G

2018-01-30

Cutaneous hyperchromias are disorders of skin pigmentation involving increased melanin production and its irregular accumulation in skin cells. The use of sunscreens is fundamental for the control of hyperchromias by reducing the stimulation of pigmentation, as melanin synthesis is mainly stimulated by solar radiation. Many studies have demonstrated that visible light can induce significant skin damage. Considering the effects of visible light, effective photoprotection should not be limited only to UV protection but should also involve visible and infrared protection. The aim of this study was to evaluate the efficacy of UV-VIS sunscreens in protecting skin against damages caused by solar radiation and the influence of visible light on the appearance of cutaneous hyperchromias. Forty volunteers aged 18 to 39 years with skin hyperpigmentation participated in the study. To evaluate the efficacy of the formulations developed, the percentage of hyperpigmented area was evaluated using high-resolution images-Visioface ® Quick (Courage-Khazaka, Germany) and the analysis of epidermal pigmentation was performed by RCM-Vivascope ® 1500 (Lucid, USA). Also, the melanin index was determined using the Mexameter ® M X16 colorimeter (Courage-Khazaka, Germany). The developed formulations were effective in the reduction in melanin index, epidermal pigmentation, and percentage of hyperpigmented area. Finally, this study discusses how the combination of UV filters and pigments can protect the skin from solar radiation and reduces skin hyperpigmentations. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals: In Vitro and In Vivo Studies and the Underlying Mechanisms

PubMed Central

Singh, Madhulika; Suman, Shankar; Shukla, Yogeshwer

2014-01-01

Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo models and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer. PMID:24757666

Atomic force imaging microscopy investigation of the interaction of ultraviolet radiation with collagen thin films

NASA Astrophysics Data System (ADS)

Stylianou, A.; Yova, D.; Alexandratou, E.; Petri, A.

2013-02-01

Collagen is the major fibrous protein in the extracellular matrix and consists a significant component of skin, bone, cartilage and tendon. Due to its unique properties, it has been widely used as scaffold or culture substrate for tissue regeneration or/and cell-substrate interaction studies. The ultraviolet light-collagen interaction investigations are crucial for the improvement of many applications such as that of the UV irradiation in the field of biomaterials, as sterilizing and photo-cross-linking method. The aim of this paper was to investigate the mechanisms of UV-collagen interactions by developing a collagen-based, well characterized, surface with controlled topography of collagen thin films in the nanoscale range. The methodology was to quantify the collagen surface modification induced on ultraviolet radiation and correlate it with changes induced in cells. Surface nanoscale characterization was performed by Atomic Force Microscopy (AFM) which is a powerful tool and offers quantitative and qualitative information with a non-destructive manner. In order to investigate cells behavior, the irradiated films were used for in vitro cultivation of human skin fibroblasts and the cells morphology, migration and alignment were assessed with fluorescence microscopy imaging and image processing methods. The clarification of the effects of UV light on collagen thin films and the way of cells behavior to the different modifications that UV induced to the collagen-based surfaces will contribute to the better understanding of cell-matrix interactions in the nanoscale and will assist the appropriate use of UV light for developing biomaterials.

Cutaneous porphyrins exhibit anti-stokes fluorescence that is detectable in sebum (Conference Presentation)

NASA Astrophysics Data System (ADS)

Tian, Giselle; Zeng, Haishan; Zhao, Jianhua; Wu, Zhenguo; Al Jasser, Mohammed; Lui, Harvey; Mclean, David I.

2016-02-01

Porphyrins produced by Propionibacterium acnes represent the principal fluorophore associated with acne, and appear as orange-red luminescence under the Wood's lamp. Assessment of acne based on Wood's lamp (UV) or visible light illumination is limited by photon penetration depth and has limited sensitivity for earlier stage lesions. Inducing fluorescence with near infrared (NIR) excitation may provide an alternative way to assess porphyrin-related skin disorders. We discovered that under 785 nm CW laser excitation PpIX powder exhibits fluorescence emission in the shorter wavelength range of 600-715 nm with an intensity that is linearly dependent on the excitation power. We attribute this shorter wavelength emission to anti-Stokes fluorescence. Similar anti-Stokes fluorescence was also detected focally in all skin-derived samples containing porphyrins. Regular (Stokes) fluorescence was present under UV and visible light excitation on ex vivo nasal skin and sebum from uninflamed acne, but not on nose surface smears or sebum from inflamed acne. Co-registered CW laser-excited anti-Stokes fluorescence and fs laser-excited multi-photon fluorescence images of PpIX powder showed similar features. In the skin samples because of the anti-Stokes effect, the NIR-induced fluorescence was presumably specific for porphyrins since there appeared to be no anti-Stokes emission signals from other typical skin fluorophores such as lipids, keratins and collagen. Anti-Stokes fluorescence under NIR CW excitation is more sensitive and specific for porphyrin detection than UV- or visible light-excited regular fluorescence and fs laser-excited multi-photon fluorescence. This approach also has higher image contrast compared to NIR fs laser-based multi-photon fluorescence imaging. The anti-Stokes fluorescence of porphyrins within sebum could potentially be applied to detecting and targeting acne lesions for treatment via fluorescence image guidance.

Potential for tyndalized Lactobacillus acidophilus as an effective component in moisturizing skin and anti-wrinkle products.

PubMed

Im, A-Rang; Kim, Hui Seong; Hyun, Jin Won; Chae, Sungwook

2016-08-01

It is widely accepted that ultraviolet (UV) irradiation induces skin damage. In the present study, a UVB-induced hairless mouse model of skin photoaging was developed to determine whether tyndalized Lactobacillus acidophilus was able to significantly enhance the repair of photodamaged skin. To evaluate the effects of tyndalized L. acidophilus on UVB-induced skin-wrinkle formation in vivo , HR-1 hairless male mice were exposed to UVB radiation and orally administered tyndalized L. acidophilus . Compared with the control group, the UVB irradiation mice displayed a significant increase in transepidermal water loss and a reduction in skin hydration. In mice with UVB-induced photodamage, the effacement of the fine wrinkles by tyndalized L. acidophilus was correlated with dermal collagen synthesis, accompanied by histological changes. Furthermore, western blotting was performed to investigate the protein expression levels of matrix metalloproteinases (MMPs) and mitogen-activated protein kinase. Notably, orally administered tyndalized L. acidophilus reduced the expression levels of MMP-1 and MMP-9. Based upon the aforementioned results, it was determined that tyndalized L. acidophilus effectively inhibited the wrinkle formation induced by UVB irradiation, and that this may be attributed to the downregulation of MMPs. Therefore, tyndalized L. acidophilus may be considered a potential agent for preventing skin photoaging and wrinkle formation.

Salvianolic Acid B Protects Normal Human Dermal Fibroblasts Against Ultraviolet B Irradiation-Induced Photoaging Through Mitogen-Activated Protein Kinase and Activator Protein-1 Pathways.

PubMed

Sun, Zhengwang; Park, Sang-Yong; Hwang, Eunson; Zhang, Mengyang; Jin, Fengxie; Zhang, Baochun; Yi, Tae Hoo

2015-01-01

Exposure to ultraviolet (UV) light causes increased matrix metalloproteinase (MMP) activity and decreased collagen synthesis, leading to skin photoaging. Salvianolic acid B (SAB), a polyphenol, was extracted and purified from salvia miltiorrhiza. We assessed effects of SAB on UVB-induced photoaging and investigated its molecular mechanism of action in UVB-irradiated normal human dermal fibroblasts. Our results show that SAB significantly inhibited the UVB-induced expression of metalloproteinases-1 (MMP-1) and interleukin-6 (IL-6) while promoting the production of type I procollagen and transforming growth factor β1 (TGF-β1). Moreover, treatment with SAB in the range of 1-100 μg/mL significantly inhibited UVB-induced extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 phosphorylation, which resulted in decreasing UVB-induced phosphorylation of c-Fos and c-Jun. These results indicate that SAB downregulates UV-induced MMP-1 expression by inhibiting Mitogen-activated protein kinase (MAPK) signaling pathways and activator protein-1 (AP-1) activation. Our results suggest a potential use for SAB in skin photoprotection. © 2015 The American Society of Photobiology.

Faster DNA Repair of Ultraviolet-Induced Cyclobutane Pyrimidine Dimers and Lower Sensitivity to Apoptosis in Human Corneal Epithelial Cells than in Epidermal Keratinocytes

PubMed Central

Mallet, Justin D.; Bastien, Nathalie; Gendron, Sébastien P.; Rochette, Patrick J.

2016-01-01

Absorption of UV rays by DNA generates the formation of mutagenic cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts (6-4PP). These damages are the major cause of skin cancer because in turn, they can lead to signature UV mutations. The eye is exposed to UV light, but the cornea is orders of magnitude less prone to UV-induced cancer. In an attempt to shed light on this paradox, we compared cells of the corneal epithelium and the epidermis for UVB-induced DNA damage frequency, repair and cell death sensitivity. We found similar CPD levels but a 4-time faster UVB-induced CPD, but not 6-4PP, repair and lower UV-induced apoptosis sensitivity in corneal epithelial cells than epidermal. We then investigated levels of DDB2, a UV-induced DNA damage recognition protein mostly impacting CPD repair, XPC, essential for the repair of both CPD and 6-4PP and p53 a protein upstream of the genotoxic stress response. We found more DDB2, XPC and p53 in corneal epithelial cells than in epidermal cells. According to our results analyzing the protein stability of DDB2 and XPC, the higher level of DDB2 and XPC in corneal epithelial cells is most likely due to an increased stability of the protein. Taken together, our results show that corneal epithelial cells have a better efficiency to repair UV-induced mutagenic CPD. On the other hand, they are less prone to UV-induced apoptosis, which could be related to the fact that since the repair is more efficient in the HCEC, the need to eliminate highly damaged cells by apoptosis is reduced. PMID:27611318