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2.
Redox Biol ; 24: 101206, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31039479

RESUMO

We tested whether novel CYP11A1-derived vitamin D3- and lumisterol-hydroxyderivatives, including 1,25(OH)2D3, 20(OH)D3, 1,20(OH)2D3, 20,23(OH)2D3, 1,20,23(OH)3D3, lumisterol, 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3, can protect against UVB-induced damage in human epidermal keratinocytes. Cells were treated with above compounds for 24 h, then subjected to UVB irradiation at UVB doses of 25, 50, 75, or 200 mJ/cm2, and then examined for oxidant formation, proliferation, DNA damage, and the expression of genes at the mRNA and protein levels. Oxidant formation and proliferation were determined by the DCFA-DA and MTS assays, respectively. DNA damage was assessed using the comet assay. Expression of antioxidative genes was evaluated by real-time RT-PCR analysis. Nuclear expression of CPD, phospho-p53, and Nrf2 as well as its target proteins including HO-1, CAT, and MnSOD, were assayed by immunofluorescence and western blotting. Treatment of cells with the above compounds at concentrations of 1 or 100 nM showed a dose-dependent reduction in oxidant formation. At 100 nM they inhibited the proliferation of cultured keratinocytes. When keratinocytes were irradiated with 50-200 mJ/cm2 of UVB they also protected against DNA damage, and/or induced DNA repair by enhancing the repair of 6-4PP and attenuating CPD levels and the tail moment of comets. Treatment with test compounds increased expression of Nrf2-target genes involved in the antioxidant response including GR, HO-1, CAT, SOD1, and SOD2, with increased protein expression for HO-1, CAT, and MnSOD. The treatment also stimulated the phosphorylation of p53 at Ser-15, increased its concentration in the nucleus and enhanced Nrf2 translocation into the nucleus. In conclusion, pretreatment of keratinocytes with 1,25(OH)2D3 or CYP11A1-derived vitamin D3- or lumisterol hydroxy-derivatives, protected them against UVB-induced damage via activation of the Nrf2-dependent antioxidant response and p53-phosphorylation, as well as by the induction of the DNA repair system. Thus, the new vitamin D3 and lumisterol hydroxy-derivatives represent promising anti-photodamaging agents.

3.
Adv Protein Chem Struct Biol ; 115: 247-295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30798934

RESUMO

Malignant melanoma of the skin is the leading cause of death from skin cancer and ranks fifth in cancer incidence among all cancers in the United States. While melanoma mortality has remained steady for the past several decades, melanoma incidence has been increasing, particularly among fair-skinned individuals. According to the American Cancer Society, nearly 10,000 people in the United States will die from melanoma this year. Individuals with dark skin complexion are protected damage generated by UV-light due to the high content of UV-blocking melanin pigment in their epidermis as well as better capacity for melanocytes to cope with UV damage. There is now ample evidence that suggests that the melanocortin 1 receptor (MC1R) is a major melanoma risk factor. Inherited loss-of-function mutations in MC1R are common in melanoma-prone persons, correlating with a less melanized skin complexion and poorer recovery from mutagenic photodamage. We and others are interested in the MC1R signaling pathway in melanocytes, its mechanisms of enhancing genomic stability and pharmacologic opportunities to reduce melanoma risk based on those insights. In this chapter, we review melanoma risk factors, the MC1R signaling pathway, and the relationship between MC1R signaling and DNA repair.


Assuntos
AMP Cíclico/metabolismo , Instabilidade Genômica , Melanócitos/metabolismo , Melanoma/genética , Melanoma/prevenção & controle , Animais , Humanos , Melanoma/metabolismo , Melanoma/patologia
4.
Pigment Cell Melanoma Res ; 31(6): 728-735, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30281213

RESUMO

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution.


Assuntos
Pesquisa Biomédica , Melanócitos/patologia , Melanoma/patologia , Animais , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Melanoma/epidemiologia , Melanoma/prevenção & controle , Melanoma/terapia , Pigmentação
5.
J Biol Chem ; 293(49): 19025-19037, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30327428

RESUMO

Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMP-mediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. SIRT1 deacetylates XPA at residues Lys-63, Lys-67, and Lys-215 to promote interactions with ATR. Mutant XPA containing acetylation mimetics at residues Lys-63, Lys-67, and Lys-215 exhibit blunted UV-dependent ATR-XPA interactions even in the presence of cAMP signals. ATR-mediated phosphorylation of XPA on Ser-196 enhances cAMP-mediated optimization of NER and is promoted by SIRT1-mediated deacetylation of XPA on Lys-63, Lys-67, and Lys-215. Interference with ATR-mediated XPA phosphorylation at Ser-196 by persistent acetylation of XPA at Lys-63, Lys-67, and Lys-215 delays repair of UV-induced DNA damage and attenuates cAMP-enhanced NER. Our study identifies a regulatory ATR-SIRT1-XPA axis in cAMP-mediated regulation melanocyte genomic stability, involving SIRT1-mediated deacetylation (Lys-63, Lys-67, and Lys-215) and ATR-dependent phosphorylation (Ser-196) post-translational modifications of the core NER factor XPA.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Reparo do DNA/fisiologia , Sirtuína 1/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , Acetilação , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Humanos , Lisina/química , Melanócitos/efeitos da radiação , Fosforilação , Processamento de Proteína Pós-Traducional , Serina/química , Raios Ultravioleta , Proteína de Xeroderma Pigmentoso Grupo A/química
6.
Sci Rep ; 7(1): 11708, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28916831

RESUMO

Using primary melanocytes and HEK293 cells, we found that cAMP signaling accelerates repair of bi- and mono-functional platinum-induced DNA damage. Elevating cAMP signaling either by the agonistic MC1R ligand melanocyte stimulating hormone (MSH) or by pharmacologic cAMP induction by forskolin enhanced clearance of intrastrand cisplatin-adducts in melanocytes or MC1R-transfected HEK293 cells. MC1R antagonists human beta-defensin 3 and agouti signaling protein blocked MSH- but not forskolin-mediated enhancement of platinum-induced DNA damage. cAMP-enhanced repair of cisplatin-induced DNA damage was dependent on PKA-mediated phosphorylation of ATR on S435 which promoted ATR's interaction with the key NER factor xeroderma pigmentosum A (XPA) and facilitated recruitment of an XPA-ATR-pS435 complex to sites of cisplatin DNA damage. Moreover, we developed an oligonucleotide retrieval immunoprecipitation (ORiP) assay using a novel platinated-DNA substrate to establish kinetics of ATR-pS435 and XPA's associations with cisplatin-damaged DNA. Expression of a non-phosphorylatable ATR-S435A construct or deletion of A kinase-anchoring protein 12 (AKAP12) impeded platinum adduct clearance and prevented cAMP-mediated enhancement of ATR and XPA's associations with cisplatin-damaged DNA, indicating that ATR phosphorylation at S435 is necessary for cAMP-enhanced repair of platinum-induced damage and protection against cisplatin-induced mutagenesis. These data implicate cAMP signaling as a critical regulator of genomic stability against platinum-induced mutagenesis.


Assuntos
AMP Cíclico/metabolismo , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Melanocortinas/fisiologia , Mutagênese/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Instabilidade Genômica/efeitos dos fármacos , Células HEK293 , Humanos , Compostos de Platina/toxicidade , Transdução de Sinais/fisiologia
8.
Exp Dermatol ; 26(7): 577-584, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28094871

RESUMO

Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia-mutated and Rad3-related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP-mediated melanin upregulation and cAMP-enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR-dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP-mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R-mediated enhancement of genome maintenance (eg PKA-mediated phosphorylation of ATR) and MC1R-induced pigment induction (eg MITF activation) are distinct.


Assuntos
AMP Cíclico/metabolismo , Reparo do DNA , Melanócitos/citologia , Receptor Tipo 1 de Melanocortina/metabolismo , Pigmentação da Pele , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dano ao DNA , Humanos , Levodopa/química , Melaninas/química , Mutagênese , Nucleotídeos/química , Fosforilação , RNA Interferente Pequeno/metabolismo , Receptor Tipo 1 de Melanocortina/genética , Serina/química , Serina/genética , Transdução de Sinais , Raios Ultravioleta , Regulação para Cima
9.
Adv Exp Med Biol ; 906: 149-165, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27628011

RESUMO

The VTE is mainly a disease of the older adult, though its incidence has increased significantly in the pediatric population over the past several years. This trend is likely due to enhanced awareness and recognition of VTE, as well as increased prevalence of thromboembolic associated risk factors, such as increases in the proportion of children with predisposing medical conditions. The evaluation and management of a child with VTE is similar to that of adults, however pediatric patients have their own distinct aspects of care, stemming from particularities of the hemostatic system, age-related risk factors and differences in response to anticoagulant and antithrombotic therapy. This review addresses the risk factors and the evaluation and management of children with VTE.


Assuntos
Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Trombectomia , Tromboembolia/terapia , Trombose Venosa/terapia , Adolescente , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/patologia , Cateteres Venosos Centrais/efeitos adversos , Criança , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/patologia , Humanos , Neoplasias/complicações , Neoplasias/diagnóstico , Neoplasias/patologia , Fatores de Risco , Sepse/complicações , Sepse/diagnóstico , Sepse/patologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Tromboembolia/diagnóstico , Tromboembolia/etiologia , Tromboembolia/cirurgia , Trombose Venosa/diagnóstico , Trombose Venosa/etiologia , Trombose Venosa/cirurgia
10.
Photochem Photobiol ; 93(1): 245-258, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27645605

RESUMO

Melanoma is the deadliest form of skin cancer because of its propensity to spread beyond the primary site of disease and because it resists many forms of treatment. Incidence of melanoma has been increasing for decades. Although ultraviolet radiation (UV) has been identified as the most important environmental causative factor for melanoma development, UV-protective strategies have had limited efficacy in melanoma prevention. UV mutational burden correlates with melanoma development and tumor progression, underscoring the importance of UV in melanomagenesis. However, besides amount of UV exposure, melanocyte UV mutational load is influenced by the robustness of nucleotide excision repair, the genome maintenance pathway charged with removing UV photoproducts before they cause permanent mutations in the genome. In this review, we highlight the importance of the melanocortin hormonal signaling axis on regulating efficiency of nucleotide excision repair in melanocytes. By understanding the molecular mechanisms by which nucleotide excision repair can be increased, it may be possible to prevent many cases of melanoma by reducing UV mutational burden over time.


Assuntos
Reparo do DNA , Melanocortinas/metabolismo , Melanócitos/metabolismo , Dímeros de Pirimidina/metabolismo , Transdução de Sinais , Raios Ultravioleta/efeitos adversos , AMP Cíclico/metabolismo , Humanos , Melanoma/epidemiologia , Receptor Tipo 1 de Melanocortina/agonistas , Receptor Tipo 1 de Melanocortina/antagonistas & inibidores , Receptor Tipo 1 de Melanocortina/metabolismo , Estados Unidos/epidemiologia , Xeroderma Pigmentoso/etiologia
11.
Nucleic Acids Res ; 44(22): 10711-10726, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27683220

RESUMO

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12-ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5' strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12-ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.


Assuntos
Proteínas de Ancoragem à Quinase A/fisiologia , Proteínas de Ciclo Celular/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA , Reparo do DNA , Células HEK293 , Humanos , Cinética , Mutagênese , Fosforilação , Transporte Proteico , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo
12.
Front Genet ; 7: 95, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27303435

RESUMO

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist ß-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory's findings on the molecular mechanisms by which MC1R signaling impacts NER.

13.
J Invest Dermatol ; 135(12): 3086-3095, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26168232

RESUMO

The melanocortin 1 receptor (MC1R), a GS-coupled receptor that signals through cAMP and protein kinase A (PKA), regulates pigmentation, adaptive tanning, and melanoma resistance. MC1R-cAMP signaling promotes PKA-mediated phosphorylation of ataxia telangiectasia and rad3-related (ATR) at Ser435 (ATR-pS435), a modification that enhances nucleotide excision repair (NER) by facilitating recruitment of the XPA protein to sites of UV-induced DNA damage. High-throughput methods were developed to quantify ATR-pS435, measure XPA-photodamage interactions, and assess NER function. We report that melanocyte-stimulating hormone (α-MSH) or ACTH induce ATR-pS435, enhance XPA's association with UV-damaged DNA and optimize melanocytic NER. In contrast, MC1R antagonists agouti signaling protein (ASIP) or human ß-defensin 3 (HBD3) interfere with ATR-pS435 generation, impair the XPA-DNA interaction, and reduce DNA repair. Although ASIP and HBD3 each blocked α-MSH-mediated induction of the signaling pathway, only ASIP depleted basal ATR-pS435. Our findings confirm that ASIP diminishes agonist-independent MC1R basal signaling whereas HBD3 is a neutral MC1R antagonist that blocks activation by melanocortins. Furthermore, our data suggest that ATR-pS435 may be a useful biomarker for the DNA repair-deficient MC1R phenotype.


Assuntos
Reparo do DNA , Melanócitos/metabolismo , Receptor Tipo 1 de Melanocortina/fisiologia , Proteína Agouti Sinalizadora/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , DNA/metabolismo , Humanos , Fosforilação , Serina/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , beta-Defensinas/farmacologia
15.
Mol Cell ; 54(6): 999-1011, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24950377

RESUMO

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.


Assuntos
Dano ao DNA , Receptor Tipo 1 de Melanocortina/genética , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos C57BL , Mutagênese/efeitos da radiação , Fosforilação/efeitos da radiação , Pigmentação/genética , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/efeitos da radiação , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Raios Ultravioleta , Proteína de Xeroderma Pigmentoso Grupo A/genética
17.
Molecules ; 19(5): 6202-19, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24838074

RESUMO

Being the largest and most visible organ of the body and heavily influenced by environmental factors, skin is ideal to study the long-term effects of aging. Throughout our lifetime, we accumulate damage generated by UV radiation. UV causes inflammation, immune changes, physical changes, impaired wound healing and DNA damage that promotes cellular senescence and carcinogenesis. Melanoma is the deadliest form of skin cancer and among the malignancies of highest increasing incidence over the last several decades. Melanoma incidence is directly related to age, with highest rates in individuals over the age of 55 years, making it a clear age-related disease. In this review, we will focus on UV-induced carcinogenesis and photo aging along with natural protective mechanisms that reduce amount of "realized" solar radiation dose and UV-induced injury. We will focus on the theoretical use of forskolin, a plant-derived pharmacologically active compound to protect the skin against UV injury and prevent aging symptoms by up-regulating melanin production. We will discuss its use as a topically-applied root-derived formulation of the Plectranthus barbatus (Coleus forskolii) plant that grows naturally in Asia and that has long been used in various Aryuvedic teas and therapeutic preparations.


Assuntos
AMP Cíclico/metabolismo , Melanoma/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Pele/patologia , Administração Tópica , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Envelhecimento/efeitos da radiação , Dano ao DNA/efeitos da radiação , Humanos , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Extratos Vegetais/química , Plectranthus/química , Pele/efeitos da radiação , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Raios Ultravioleta
18.
Endocr Relat Cancer ; 21(3): R209-25, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24500760

RESUMO

Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Estilbenos/uso terapêutico , Animais , Humanos , Resveratrol
19.
J Vis Exp ; (79)2013 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-24056496

RESUMO

Fairness of skin, UV sensitivity and skin cancer risk all correlate with the physiologic function of the melanocortin 1 receptor, a Gs-coupled signaling protein found on the surface of melanocytes. Mc1r stimulates adenylyl cyclase and cAMP production which, in turn, up-regulates melanocytic production of melanin in the skin. In order to study the mechanisms by which Mc1r signaling protects the skin against UV injury, this study relies on a mouse model with "humanized skin" based on epidermal expression of stem cell factor (Scf). K14-Scf transgenic mice retain melanocytes in the epidermis and therefore have the ability to deposit melanin in the epidermis. In this animal model, wild type Mc1r status results in robust deposition of black eumelanin pigment and a UV-protected phenotype. In contrast, K14-Scf animals with defective Mc1r signaling ability exhibit a red/blonde pigmentation, very little eumelanin in the skin and a UV-sensitive phenotype. Reasoning that eumelanin deposition might be enhanced by topical agents that mimic Mc1r signaling, we found that direct application of forskolin extract to the skin of Mc1r-defective fair-skinned mice resulted in robust eumelanin induction and UV protection (1). Here we describe the method for preparing and applying a forskolin-containing natural root extract to K14-Scf fair-skinned mice and report a method for measuring UV sensitivity by determining minimal erythematous dose (MED). Using this animal model, it is possible to study how epidermal cAMP induction and melanization of the skin affect physiologic responses to UV exposure.


Assuntos
Colforsina/administração & dosagem , Glicoproteínas/biossíntese , Pele/efeitos dos fármacos , Pele/metabolismo , Queimadura Solar/metabolismo , Queimadura Solar/prevenção & controle , Toxinas Biológicas/biossíntese , Animais , Colforsina/química , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/efeitos da radiação , Eritema/etiologia , Eritema/prevenção & controle , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Raízes de Plantas/química , Plectranthus/química , Tolerância a Radiação , Pele/efeitos da radiação , Pigmentação da Pele/efeitos dos fármacos , Raios Ultravioleta
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