Morfologia, taxa de crescimento e expressão gênica de fibroblastos no melasma facial

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Botucatu, SP, Brasil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Patologia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Autor para correspondência." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3055 "Ancho" => 1508 "Tamanyo" => 194628 ] ] "descripcion" => array:1 [ "pt" => "Fold change (Log2 média e 95% IC) da expressão gênica entre a pele com melasma e a pele sã adjacente avaliada por real‐time PCR array (n = 5)." ] ] ] "textoCompleto" => "IntroduçãoMelasma é discromia adquirida e de elevada prevalência, que decorre de aumento na atividade da unidade epidermo‐melânica.<a class="elsevierStyleCrossRef" href="#bib0205">1</a> As lesões acometem áreas fotoexpostas (por exemplo, a face), principalmente em mulheres durante o menacme. Sua patogênese ainda não é totalmente compreendida; o papel das alterações da zona da membrana basal, danos à derme superior e atividade dos fibroblastos no desenvolvimento da doença são questões de pesquisas recentes.<a class="elsevierStyleCrossRefs" href="#bib0210">2–5</a>Em comparação com a pele sã adjacente (fotoexposta), a pele com melasma apresenta aumento na quantidade de melanina epidérmica, melanossomas mais maduros, melanócitos hipertrofiados e elastose solar proeminente. Também há um aumento no número de vasos e de mastócitos, bem como expressão aumentada de mediadores inflamatórios, como iNOS, NF‐Kβ, endotelina, e fatores de crescimento, como VEGF, fator de crescimento derivado de hepatócitos, de stem cell, de fibroblastos e de nervos.<a class="elsevierStyleCrossRef" href="#bib0230">6</a> Melanócitos em pêndulo – melanócitos da camada basal que se projetam em direção à derme superior – e alterações na membrana basal também foram descritos no melasma.<a class="elsevierStyleCrossRef" href="#bib0210">2</a> Há diminuição do colágeno tipo I associada a aumento na atividade de metaloproteinases (MMP 1, 2, 3 e 9).<a class="elsevierStyleCrossRef" href="#bib0235">7</a> Alguns genes relacionados ao metabolismo lipídico estão regulados negativamente na pele do melasma e a função da barreira cutânea é prejudicada.<a class="elsevierStyleCrossRef" href="#bib0240">8</a>A exposição solar é o principal fator de risco para o desenvolvimento do melasma. A fotoexposição crônica, além da melanogênese, induz estresse oxidativo, o que promove senescência celular.<a class="elsevierStyleCrossRef" href="#bib0225">5</a> Além do fotoenvelhecimento e do envelhecimento intrínseco, o melasma apresenta um fenótipo senescente mais proeminente na pele acometida. A senescência celular precoce induzida pela radiação ultravioleta (RUV) promove alterações funcionais que podem deflagrar e perpetuar a melanogênese.<a class="elsevierStyleCrossRefs" href="#bib0245">9,10</a>Os fibroblastos têm um papel central na pigmentação, e sua transição para perfil senescente promove modificação de suas atividades autócrina e parácrina.<a class="elsevierStyleCrossRef" href="#bib0250">10</a> Na pele com melasma, os fibroblastos liberam mais fator derivado de stem cell e seu receptor epidérmico c‐kit.<a class="elsevierStyleCrossRef" href="#bib0255">11</a> Fibroblastos senescentes podem expressar fatores inflamatórios e melanogênicos, o que pode levar ao desenvolvimento do melasma.<a class="elsevierStyleCrossRef" href="#bib0215">3</a>O fenótipo senescente foi identificado nos fibroblastos com melasma de maneira mais intensa que na pele adjacente fotoexposta a partir da imunoexpressão de p16INK4A, o que pode justificar o estímulo para a pigmentação cutânea sustentada.<a class="elsevierStyleCrossRefs" href="#bib0245">9,10</a> Porém, até o momento, não foi explorado o potencial de replicação celular, ou caracterizado o perfil de expressão gênica desses fibroblastos dérmicos, no que se refere a fatores de crescimento e reparo tecidual, ativação da via de crescimento tecidual WNT/β‐catenina (WNT), neocolagênese, síntese de metaloproteinases, receptores de estrogênios e mecanismos antioxidantes. Tal caracterização pode subsidiar modelos fisiopatológicos e estratégias de tratamento.Este estudo teve como objetivo explorar a morfologia, a taxa de crescimento e o perfil de expressão gênica de fibroblastos oriundos do melasma facial, em comparação com a pele adjacente fotoexposta.MétodosEste projeto foi aprovado pelo Conselho de Ética em Pesquisa (Unesp, Botucatu‐SP, n.° 0461‐11) e todos os participantes consentiram em participar.Dez mulheres adultas com melasma facial foram biopsiadas (punch 2 mm, utilizando técnica estéril) na pele com melasma da região malar e na pele fotoexposta adjacente clinicamente normal (< 2 cm de distância), lateralmente. As participantes estavam sem tratamento para a dermatose por pelo menos 30 dias, exceto pelo uso de protetor solar.Os fragmentos de pele foram seccionados e colocados em cultura de fibroblastos, mantidos em meio 106 (GibcoTM) contendo fatores de crescimento (LSGS Kit, GibcoTM). Os fibroblastos foram semeados (em triplicada) a uma densidade de 5×10<a class="elsevierStyleCrossRef" href="#bib0215">3</a> em placa de cultura celular de 12 poços.Fibroblastos cultivados, de pele sã e lesada, de cinco participantes foram semeados a uma densidade de 1 × 104 em placa de cultura celular de seis poços, e o número de células por cm2 foi avaliado após 2, 5 e 8 dias, a partir da avaliação de 30 campos, e comparados (entre as topografias) por modelo linear generalizado de efeitos mistos. A normalidade das amostras foi avaliada pelo teste de Shapiro‐Wilk.Posteriormente, a senescência celular foi avaliada por meio de senescence β‐galactosidase (SA‐β‐gal) staining kit (Cell Signaling Technology®), seguindo as instruções do fabricante. Após 24 horas do plaqueamento das células, foi removido o meio de cultura, seguiu‐se com lavagem com PBS e adição de solução de fixação por 15 minutos à temperatura ambiente. Então, realizou‐se lavagem com PBS por duas vezes e incubação overnight com solução de β‐galactosidase (Cell Signaling Technology®), a 37°C. Após remoção da solução, foi adicionado glicerina 70%.Foram contadas 300 células por amostra. A morfologia dos fibroblastos em cultura e o percentual de células marcadas com SA‐β‐gal citoplasmático foram comparados entre as topografias (melasma e pele sã adjacente).Fibroblastos da cultura celular primária das outras cinco participantes foram submetidos a real‐time PCR array (placa de 96 poços, Custom RT2Profiler PCR Arrays, Qiagen) para avaliar a expressão de 39 genes associados a fatores de crescimento e reparo tecidual, ativação da via WNT, neocolagênese, síntese de metaloproteinases, receptores de estrogênios e mecanismos antioxidantes. (<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>). O RNA total foi obtido com RNase mini kit (Qiagen), e a transcrição reversa do RNA foi realizada utilizando RT2First Strand Kit for RT‐PCR (Qiagen), seguindo as instruções do fabricante.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>O tamanho do efeito para a expressão gênica (2−ΔΔCt) foi estimado pelo fold change (melasma/pele adjacente) para cada participante.<a class="elsevierStyleCrossRef" href="#bib0260">12</a> Os fold changes foram representadas por sua média e 95% IC, estimados por 10.000 reamostragens com correção acelerada de viés (accelerated bias correction – BCa).ResultadosOs principais dados clínicos e demográficos dos pacientes estudados estão dispostos na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Em todas as amostras, as culturas de fibroblastos da pele do melasma foram de menor densidade celular, e morfologicamente menos alongados, mais largos, menos fusiformes, além de apresentar mais células marcadas com SA‐β‐gal (superioridade média de 34%; 95% IC 4‐63%; p < 0,05) do que as culturas oriundas da pele adjacente (<a class="elsevierStyleCrossRefs" href="#fig0005">figs. 1 e 2</a>). Além disso, a taxa de crescimento celular foi menor para as amostras de melasma após oito dias em cultura (p < 0,01) (<a class="elsevierStyleCrossRef" href="#fig0015">fig. 3</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Foram identificadas alterações na expressão gênica dos fibroblastos isoladas da pele com melasma em comparação com aqueles isoladas da pele sã adjacente. Os genes WNT3A, EDN3, ESR2, PTG2, MMP1 e SOD2 estavam regulados positivamente (up‐regulated); já os genes COL4A1, CSF2, DKK3, COL7A1, TIMP4, CCL2 e CDH11 estavam regulados negativamente (down‐regulated) (<a class="elsevierStyleCrossRef" href="#fig0020">fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>DiscussãoA melanogênese é processo complexo mediado por estímulos parácrinos, autócrinos e ambientais.<a class="elsevierStyleCrossRef" href="#bib0265">13</a> As alterações fenotípicas evidenciadas na pele com melasma não decorrem primariamente ou unicamente de alteração epidérmica, uma vez que diversas alterações dérmicas são evidentes na pele acometida em comparação com a pele fotoexposta sã adjacente.<a class="elsevierStyleCrossRef" href="#bib0270">14</a>O fibroblasto é o tipo celular mais comum na derme e, em virtude de sua grande longevidade, acumula danos em seu maquinário celular, que podem resultar em alterações funcionais e morfológicas.<a class="elsevierStyleCrossRef" href="#bib0250">10</a> O envelhecimento intrínseco e o fotoenvelhecimento estão associados à diminuição no número e na taxa de proliferação de fibroblastos; neste contexto, a comparação do perfil gênico de fibroblastos oriundos da pele com melasma com o de área fotoexposta adjacente sã reforça que as alterações gênicas são independentes da idade e da fotoexposição.<a class="elsevierStyleCrossRefs" href="#bib0215">3,15</a>Considerando a importância dos fibroblastos dérmicos na regulação da pigmentação, as modificações de suas atividades autócrinas e parácrinas podem influenciar as desordens pigmentares.<a class="elsevierStyleCrossRef" href="#bib0250">10</a> Neste estudo, identificamos perda da morfologia fusiforme, maior quantidade de SA‐β‐gal citoplasmático e menor taxa de crescimento nos fibroblastos da pele com melasma. Essas alterações morfológicas e metabólicas endossam um fenótipo senescente nos fibroblastos da pele com melasma.A senescência é fator central nos mecanismos de envelhecimento, e o fenótipo secretor associado à senescência (senescence‐associated secretory phenotype ‐ SASP) é conhecido por ser o principal desencadeante dos fenótipos relacionados à idade, como rugas e pigmentação.<a class="elsevierStyleCrossRef" href="#bib0280">16</a> Deve‐se ressaltar que há evidências sobre diferenças fenotípicas relacionadas à etnia e suscetibilidade à senescência de fibroblastos.<a class="elsevierStyleCrossRef" href="#bib0285">17</a>Fibroblastos senescentes secretam citocinas inflamatórias e stem cell factor, que promovem a degradação do colágeno por meio da ativação de MMPs, e têm potencial mitótico reduzido. Há aumento da degradação do estroma e comprometimento no reparo tecidual, conforme evidenciado na derme do melasma. Portanto, uma estrutura em mosaico de suscetibilidade tecidual à senescência pode ser teorizada para o desenvolvimento do melasma em uma pele sob estímulos ambientais, como radiação UV, e hormônios sexuais.<a class="elsevierStyleCrossRef" href="#bib0290">18</a>Houve aumento da expressão gênica de MMP1 e diminuição da expressão dos colágenos IV, VII (COL4A1, COL7A1) e TIMP4 nos fibroblastos isolados da pele com melasma. Durante o processo de senescência, há aumento progressivo da produção de metaloproteinase e diminuição do processo de reparo.<a class="elsevierStyleCrossRef" href="#bib0250">10</a> Além disso, nos fibroblastos dérmicos, o α‐MSH promove upregulation da colagenase intersticial e atenua a síntese de colágeno induzida por TGFβ1. Já os danos à derme superior e à zona da membrana basal facilitam o trânsito de fatores melanogênicos para a camada basal. Neste estudo, apesar de uma implicação marginal, MMP9 demonstrou uma alta fold change (> 2), o que, em associação com a expressão mais baixa de TIMP1 e 4, sugere participação dos fibroblastos da pele com melasma no reparo deficiente da derme superior e angiogênese.O papel dos hormônios sexuais na expressão cutânea do receptor de estrógeno β no melasma está bem estabelecido.<a class="elsevierStyleCrossRef" href="#bib0295">19</a> Em geral, o ESR2 é expresso durante o processo de reparo.<a class="elsevierStyleCrossRef" href="#bib0300">20</a> A derme superior e a membrana basal estão muito danificadas na pele com melasma, em comparação com a pele fotoexposta adjacente sã e a pele fotoprotegida.<a class="elsevierStyleCrossRefs" href="#bib0205">1,14</a> Além disso, o estrógeno, α‐MSH e HGF estimulam a melanogênese pela ligação direta ao receptor do melanócito e também são liberados durante o processo de cicatrização de feridas.<a class="elsevierStyleCrossRefs" href="#bib0305">21,22</a> Esses achados indicam que o processo crômico e malsucedido de reparo da derme superior pode induzir melanogênese no melasma.Alguns genes relacionados à via Wnt/β‐catenina apresentaram comportamento distinto nos fibroblastos de pele com melasma em relação a pele adjacente fotoexposta; o fator inibitório DKK3 apresentou down‐regulation, enquanto WNT3A estava superexpresso. WNT3A desempenha um papel importante no controle da proliferação e diferenciação de precursores de melanócitos e angiogênese. Em melanócitos maduros, o WNT3A aumenta a quantidade de melanina e a atividade da tirosinase.<a class="elsevierStyleCrossRef" href="#bib0315">23</a> A via Wnt está envolvida na fisiopatologia do melasma, e a diminuição da expressão do fator inibitório DKK3 nos fibroblastos pode influenciar a ativação epidérmica de WNT1.<a class="elsevierStyleCrossRef" href="#bib0220">4</a> Além disso, WNT3A é importante para o processo de reparo tecidual, podendo ser ativado em decorrência dos danos à derme superior.<a class="elsevierStyleCrossRef" href="#bib0320">24</a>EDN3 é peptídeo de 21 aminoácidos e ativa preferencialmente EDNRB.<a class="elsevierStyleCrossRef" href="#bib0325">25</a> A sinalização de EDN3 é importante no desenvolvimento normal dos melanócitos da epiderme e da coroide, atuando durante a proliferação, diferenciação e sobrevivência celular.<a class="elsevierStyleCrossRef" href="#bib0330">26</a> Queratinócitos expostos ao ultravioleta B aumentam a produção e a secreção de EDN, fazendo com que os melanócitos adjacentes ativem a cascata melanogênica. Além disso, melanócitos expostos a essa mesma radiação têm aumento na expressão de c‐KIT e EDNRB.<a class="elsevierStyleCrossRef" href="#bib0330">26</a> EDN3 também participa da quimiotaxia de fibroblastos, independentemente de prolongar a sobrevivência e diferenciação celular.<a class="elsevierStyleCrossRef" href="#bib0335">27</a>Fibroblastos senescentes estão associados à deficiência nas respostas imunológicas e na supressão tumoral da pele, mas o SASP pode variar entre os tecidos e tipos de estímulo.<a class="elsevierStyleCrossRef" href="#bib0340">28</a> O CSF participa do crescimento, da diferenciação e da sobrevivência dos melanócitos, bem como do recrutamento de células‐tronco. Queratinócitos expostos à RUV do tipo A in vitro apresentam um nível mais elevado de CSF.<a class="elsevierStyleCrossRef" href="#bib0345">29</a> Além disso, a IL‐1 produzida por queratinócitos induz fibroblastos a sintetizar CSF, o que promove a proliferação e a diferenciação de queratinócitos. Uma diminuição de CSF nos fibroblastos senescentes pode configurar redução nos estímulos aos queratinócitos, o que dificulta o reparo ao tecido danificado.<a class="elsevierStyleCrossRef" href="#bib0350">30</a>CCL2 é quimiocina que atua como regulador crítico no recrutamento de macrófagos e células‐tronco durante a cicatrização de feridas, no câncer e em infecções.<a class="elsevierStyleCrossRef" href="#bib0355">31</a> Após a estimulação celular com lipopolissacarídeo, há uma down‐regulation constitucional de CCL2 nos melanócitos de indivíduos melanodérmicos em comparação com os melanócitos de indivíduos de fototipo baixo.<a class="elsevierStyleCrossRef" href="#bib0360">32</a> O perfil de expressão de CCL2 nos fibroblastos pode induzir o fenótipo focal mais escuro do melasma.As proteínas da família das caderinas desempenham papel importante na regulação da adesão intercelular e na síntese da matriz extracelular, além de contribuírem para a sinalização de eventos que controlam a homeostase celular.<a class="elsevierStyleCrossRef" href="#bib0365">33</a> Nos fibroblastos da pele, CDH11 regula a síntese de colágeno e elastina, e sua down‐regulation pode influenciar uma diminuição no reparo da derme na pele com melasma.<a class="elsevierStyleCrossRef" href="#bib0370">34</a>A superóxido dismutase (SOD) é parte do sistema antioxidante enzimático e é a principal enzima responsável pela depuração dos radicais livres de oxigênio, por meio da conversão de ânions superóxido em peróxido de hidrogênio e oxigênio.<a class="elsevierStyleCrossRef" href="#bib0375">35</a> A SOD é um complexo de enzimas intracelulares, e o nível sérico de SOD é maior entre os pacientes com melasma quando comparados aos controles, o que indica aumento do estado oxidativo sistêmico e reforça o uso de antioxidantes no tratamento do melasma.<a class="elsevierStyleCrossRef" href="#bib0380">36</a> SOD2 é uma enzima mitocondrial tetramérica que contém manganês e é direcionada ao espaço intermembrana mitocondrial. O aumento de SOD2 identificado nos fibroblastos é induzido por ambiente de estresse oxidativo e pode ser resultado de múltiplas citocinas inflamatórias; além disso, é um fenótipo característico em fibroblastos senescentes.<a class="elsevierStyleCrossRefs" href="#bib0375">35,37</a>A célula cutânea que mais contém PTGS é o fibroblasto. Essa enzima participa da síntese de prostaglandina E2 (PGE2) a partir do ácido araquidônico, e a PGE2 inibe in vitro a produção de colágeno pelos fibroblastos.<a class="elsevierStyleCrossRef" href="#bib0390">38</a> A indução de PTGS é notável em células senescentes, que aumentam a liberação de PGE2, levando a redução na síntese de colágeno tipo I, vasodilatação e quimiotaxia.<a class="elsevierStyleCrossRef" href="#bib0390">38</a> Além disso, o PGE2 pode induzir diretamente a melanogênese e aumento de dendritos nos melanócitos após irradiação com UV.<a class="elsevierStyleCrossRefs" href="#bib0395">39,40</a> O fenótipo pró‐inflamatório dos fibroblastos no melasma pode induzir dano à derme superior e uma melanogênese sustentada.Este estudo tem limitações relacionadas ao pequeno tamanho amostral e à falta de ensaios proteômicos ou funcionais para confirmar os achados. No entanto, os resultados foram consistentes e permitiram explorar, de modo preliminar, a hipótese sobre o papel dos fibroblastos na patogênese do melasma, prospectando novas investigações ligadas à patogênese e estratégias terapêuticas do melasma. A amostra de pacientes submetida ao ensaio de senescência e de proliferação foi diferente da submetida à comparação da expressão gênica, apesar de os resultados serem paralelos. Finalmente, a investigação de fibroblastos oriundos de controles sem melasma, pareados por idade, padrão de fotoexposição, fotoenvelhecimento e fototipo, poderia também elucidar a respeito da suscetibilidade individual dos fibroblastos de portadoras de melasma à senescência.Novos estudos devem investigar os fatores regulatórios dessas vias e a rede de citocinas entre queratinócitos, melanócitos, nervos, endotélio e fibroblastos no melasma, preferencialmente por meio de estudos com culturas teciduais, para experimentos genômicos, proteômicos e funcionais.ConclusõesOs fibroblastos da pele com melasma apresentaram menor taxa de crescimento, morfologia menos fusiforme e maior acúmulo de SA‐β‐gal do que os da pele fotoexposta sã adjacente. Além disso, seu perfil de expressão gênica compreendeu fatores pró‐inflamatórios, pró‐melanogênicos e relacionados ao déficit de reparo tecidual, o que pode induzir dano à derme superior e sustentar o fenótipo pigmentar focal no melasma.FinanciamentoFAPESP – n° 2012/09233‐5, 2012/05004‐1; CNPq – n° 401309/2016‐9.Contribuição dos autoresAna Cláudia Cavalcante Espósito: Concepção e planejamento do estudo; Obtenção, análise e interpretação dos dados; Redação do artigo; Revisão crítica de literatura; Aprovação da versão final do manuscrito.Gabrielli Brianezi: Concepção e planejamento do estudo; obtenção, análise e interpretação dos dados; aprovação da versão final do manuscrito.Luciane Donida Bartoli Miot: Concepção e planejamento do estudo; obtenção, análise e interpretação dos dados; participação efetiva na orientação da pesquisa; aprovação da versão final do manuscrito.Hélio Amante Miot: Concepção e planejamento do estudo; obtenção, análise e interpretação dos dados; análise estatística; redação do artigo; revisão crítica de literatura; revisão crítica do manuscrito; aprovação da versão final do manuscrito.Conflito de interessesNenhum." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1767848" "titulo" => "Resumo" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Fundamentos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Limitações do estudo" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusões" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1554160" "titulo" => "Palavras‐chave" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introdução" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Métodos" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Resultados" ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussão" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusões" ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Financiamento" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Contribuição dos autores" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflito de interesses" ] 10 => array:1 [ "titulo" => "Referências" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-08-04" "fechaAceptado" => "2021-09-15" "PalabrasClave" => array:1 [ "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras‐chave" "identificador" => "xpalclavsec1554160" "palabras" => array:5 [ 0 => "Colágeno" 1 => "Envelhecimento" 2 => "Melasma" 3 => "Raios ultravioleta" 4 => "Transtornos da pigmentação" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "FundamentosNo melasma, além da hiperfunção melanocítica, evidenciam‐se alterações na derme superior e, fibroblastos exercem função central na síntese de colágeno e na indução da pigmentação. ObjetivoExplorar a morfologia, a taxa de crescimento e o perfil de expressão gênica dos fibroblastos da pele com melasma em comparação com fibroblastos da pele sã adjacente. MétodosDez mulheres com melasma facial foram biopsiadas (lesão e pele sã adjacente), e os fragmentos foram processados para cultura de fibroblastos. Amostras de cinco participantes foram semeadas para avaliação das curvas de crescimento (dias 2, 5 e 8) e senescência (SA‐β‐gal). Amostras das demais participantes foram submetidas a real‐time PCR para avaliar comparativamente a expressão de 39 genes. ResultadosFibroblastos das culturas da pele com melasma eram morfologicamente menos fusiformes e tinham uma proporção média 34% (95% IC 4‐63%) maior de células marcadas com SA‐β‐gal do que os fibroblastos da pele adjacente. A taxa de crescimento celular foi menor para as amostras de melasma após oito dias (p < 0,01). Os genes WNT3A, EDN3, ESR2, PTG2, MMP1 e SOD2 estavam sobreregulados; já COL4A1, CSF2, DKK3, COL7A1, TIMP4, CCL2 e CDH11 estavam subregulados nos fibroblastos da pele com melasma em comparação com os da pele sã adjacente. Limitações do estudoPequeno tamanho amostral; ausência de ensaios funcionais. ConclusõesFibroblastos da pele com melasma revelaram menor taxa de crescimento, morfologia menos fusiforme e maior acúmulo de SA‐β‐gal do que os da pele fotoexposta adjacente. Além disso, seu perfil de expressão gênica compreendeu fatores que podem contribuir para dano à derme superior e melanogênese sustentada." "secciones" => array:6 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Fundamentos" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Limitações do estudo" ] 5 => array:2 [ "identificador" => "abst0030" "titulo" => "Conclusões" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Como citar este artigo: Espósito ACC, Brianezi G, Miot LDB, Miot HA. Fibroblast morphology, growth rate and gene expression in facial melasma. An Bras Dermatol. 2022;97:575–82." ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "Trabalho realizado no Departamento de Dermatologia e Radioterapia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2489 "Ancho" => 1508 "Tamanyo" => 207108 ] ] "descripcion" => array:1 [ "pt" => "Microscopia de contraste de fase exibindo fibroblastos da pele com melasma facial (A) e da pele sã adjacente (B) em cultura celular (SA‐β‐gal, 400×), evidenciando menor densidade celular e morfologia menos alongada (fusiforme), mais larga, no melasma." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1045 "Ancho" => 1508 "Tamanyo" => 134452 ] ] "descripcion" => array:1 [ "pt" => "Em ampliação da Figura 1A (1000×): morfologia senescente dos fibroblastos da pele com melasma, evidenciando maior proporção de corpos justanucleares (seta preta), estruturas citoplasmáticas (SA‐β‐gal +) granulares frequentes (seta branca), gotículas de lipídeos (cabeça de seta branca), e nucléolos segmentados (cabeça de seta preta)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figura 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1363 "Ancho" => 1508 "Tamanyo" => 86743 ] ] "descripcion" => array:1 [ "pt" => "Curvas de crescimento dos fibroblastos (contagem de células por cm<a class="elsevierStyleCrossRef" href="#bib0210">2</a>) para cinco pacientes: pele sã e com melasma facial. Barra linha horizontal representa a média de cada amostra. Dados comparados longitudinalmente por modelo linear generalizado de efeitos mistos." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figura 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 3055 "Ancho" => 1508 "Tamanyo" => 194628 ] ] "descripcion" => array:1 [ "pt" => "Fold change (Log2 média e 95% IC) da expressão gênica entre a pele com melasma e a pele sã adjacente avaliada por real‐time PCR array (n = 5)." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabela 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nome \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Função principal (cutânea) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CCL2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Quimiocina ligante C‐C tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Quimiocina envolvida no processo de reparo tecidual \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CDH11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Caderina 11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relacionada à adesão celular e reparo epitelial \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CDKN2A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidora de quinase dependente de ciclina 2a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta celular ao estímulo inflamatório e neoplásico \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COL4A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colágeno tipo IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Componente da membrana basal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">COL7A1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Colágeno tipo VII \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Componente das fibrilas de ancoragem \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSF2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator estimulador de colônias tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Envolvida no processo de reparo do epitélio \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DKK1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína relacionada ao Dickkopf 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da via de crescimento celular Wnt/β‐catenina \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DKK3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína relacionada ao Dickkopf 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da via de crescimento celular Wnt/β‐catenina \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EDN1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Endotelina tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induz melanogênese e proliferação vascular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EDN3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Endotelina tipo 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induz melanogênese e proliferação vascular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESR1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Receptor de estrogênio tipo 1 (α) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Receptor de estrogênio ligado à via canônica \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ESR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Receptor de estrogênio tipo 2 (β) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Receptor de estrogênio ligado ao reparo tecidual \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">FGF2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator de crescimento de fibroblastos tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reparo do dano tecidual, mitótico para fibroblastos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GLB1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Beta‐galactosidase tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gene constitucional. Controle do experimento \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HGF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator de crescimento hepático \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reparo do dano tecidual \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL1A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleucina 1a \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta inflamatória primária da pele \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL1B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleucina 1b \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta inflamatória primária da pele \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleucina 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta inflamatória primária da pele \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína‐quinase ativada por mitógeno 14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta celular ao estímulo inflamatório \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MIF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator de inibição da migração de macrófago \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta inflamatória primária da pele \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metaloproteinase tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradação dos colágenos tipo I, II e III \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metaloproteinase tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradação do colágeno tipo IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metaloproteinase tipo 7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradação da matriz extracelular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metaloproteinase tipo 9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradação da matriz extracelular e angiogênese \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NGR1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neuroregulina tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regula o crescimento melanocítico e cor da pele \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OXR1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína de resistência oxidativa tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta celular ao estresse oxidativo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OXSR1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína de estresse oxidativo tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Resposta celular ao estresse oxidativo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTGS2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ciclo‐oxigenase tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Síntese de prostaglandina E2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SOD1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superóxido dismutase tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protege a célula das espécies ativas de oxigênio \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SOD2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Superóxido dismutase tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induzida em resposta ao estresse oxidativo mitocondrial \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TIMP1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da metaloproteinase tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da degradação dos colágenos I, II e III \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TIMP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da metaloproteinase tipo 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da degradação do colágeno IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TIMP3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da metaloproteinase tipo 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da degradação do colágeno e matriz extracelular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TIMP4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da metaloproteinase tipo 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibidor da degradação da matriz extracelular \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TP53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteína p53 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Marcador de fotoagressão UVB, antiangiogênico \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VEGFA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator de crescimento endotelial tipo A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Promotor da angiogênese \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WIF1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fator inibidor WNT tipo 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inibe a via de crescimento celular Wnt / β‐catenina \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WNT3A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Membro 3A da família WNT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ativador da via canônica Wnt / β‐catenina \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WNT5A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Membro 5A da família WNT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ativador da via não‐canônica Wnt \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "pt" => "Lista dos 39 genes explorados no estudo, e sua função principal na pele" ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Tabela 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Tabela " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Mmasi, Índice de gravidade do melasma (modificado)." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="6" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Curva de crescimento, morfologia e marcação SA‐β‐gal</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Caso \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Idade \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fototipo \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tempo de melasma (anos) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">História familiar de melasma \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">mMASI \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8,2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12,4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Teste de expressão gênica</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">23 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9,9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19,2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9,5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sim \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7,6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Não \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10,1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "pt" => "Principais características das dez pacientes com melasma facial submetidas à biópsia da face na região com melasma malar e pele facial fotoexposta adjacente, cujas amostras foram utilizadas para curva de crescimento, morfologia e marcação SA‐β‐gal, ou teste de expressão gênica" ] ] ] "bibliografia" => array:2 [ "titulo" => "Referências" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Exploratory Study of Epidermis, Basement Membrane Zone Upper Dermis Alterations and Wnt Pathway Activation in Melasma Compared to Adjacent and Retroauricular Skin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.C.C. Espósito" 1 => "G. Brianezi" 2 => "N.P. Souza" 3 => "L.D.B. Miot" 4 => "H.A. Miot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5021/ad.2020.32.2.101" "Revista" => array:6 [ "tituloSerie" => "Ann Dermatol." "fecha" => "2020" "volumen" => "32" "paginaInicial" => "101" "paginaFinal" => "108" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33911720" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0210" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ultrastructural characterization of damage in the basement membrane of facial melasma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.C.C. Esposito" 1 => "G. Brianezi" 2 => "N.P. De Souza" 3 => "D.C. Santos" 4 => "L.D.B. Miot" 5 => "H.A. Miot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00403-019-01979-w" "Revista" => array:6 [ "tituloSerie" => "Arch Dermatol Res." "fecha" => "2019" "volumen" => "312" "paginaInicial" => "223" "paginaFinal" => "227" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31531731" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0215" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of fibroblast‐derived factors in the pathogenesis of melasma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.W. Byun" 1 => "I.S. Park" 2 => "G.S. Choi" 3 => "J. Shin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ced.12874" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Dermatol." "fecha" => "2016" "volumen" => "41" "paginaInicial" => "601" "paginaFinal" => "609" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27416970" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0220" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Exploring pathways for sustained melanogenesis in facial melasma: an immunofluorescence study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.C.C. Esposito" 1 => "G. Brianezi" 2 => "N.P. Souza" 3 => "L.D.B. Miot" 4 => "H.A. Miot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ics.12468" "Revista" => array:6 [ "tituloSerie" => "Int J Cosmet Sci." "fecha" => "2018" "volumen" => "40" "paginaInicial" => "420" "paginaFinal" => "424" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29846953" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0225" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Repeated exposure of human fibroblasts to UVR induces secretion of stem cell factor and senescence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Shin" 1 => "J.H. Kim" 2 => "E.K. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1468-3083.2011.04223.x" "Revista" => array:6 [ "tituloSerie" => "J Eur Acad Dermatol Venereol." "fecha" => "2012" "volumen" => "26" "paginaInicial" => "1577" "paginaFinal" => "1580" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21929554" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0230" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Melasma pathogenesis and influencing factors ‐ an overview of the latest research" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T. Passeron" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jdv.12049" "Revista" => array:6 [ "tituloSerie" => "J Eur Acad Dermatol Venereol." "fecha" => "2013" "volumen" => "27" "paginaInicial" => "5" "paginaFinal" => "6" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23205539" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0235" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Recent progress in melasma pathogenesis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A.Y. Lee" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/pcmr.12404" "Revista" => array:6 [ "tituloSerie" => "Pigment Cell Melanoma Res." "fecha" => "2015" "volumen" => "28" "paginaInicial" => "648" "paginaFinal" => "660" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26230865" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0240" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Defective barrier function in melasma skin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "D.J. Lee" 1 => "J. Lee" 2 => "J. Ha" 3 => "K.-C. Park" 4 => "J.-P. Ortonne" 5 => "H.Y. Kang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1468-3083.2011.04337.x" "Revista" => array:6 [ "tituloSerie" => "J Eur Acad Dermatol Venereol." "fecha" => "2012" "volumen" => "26" "paginaInicial" => "1533" "paginaFinal" => "1537" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22077137" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0245" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Senescent fibroblasts in melasma pathophysiology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M. Kim" 1 => "S.M. Kim" 2 => "S. Kwon" 3 => "T.J. Park" 4 => "H.Y. Kang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/exd.13814" "Revista" => array:6 [ "tituloSerie" => "Exp Dermatol." "fecha" => "2019" "volumen" => "28" "paginaInicial" => "719" "paginaFinal" => "722" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30575141" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0250" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Premature cell senescence in human skin: Dual face in chronic acquired pigmentary disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "B. Bellei" 1 => "M. Picardo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arr.2019.100981" "Revista" => array:5 [ "tituloSerie" => "Ageing Res Rev." "fecha" => "2020" "volumen" => "57" "paginaInicial" => "100981" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31733332" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0255" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Kim J‐Y" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H.Y. Kang" 1 => "J.S. Hwang" 2 => "J.Y. Lee" 3 => "J.H. Ahn" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lee E‐S, et al. The dermal stem cell factor and c‐kit are overexpressed in melasma. Br J Dermatol." "fecha" => "2006" "volumen" => "154" "paginaInicial" => "1094" "paginaFinal" => "1099" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0260" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of relative gene expression data using real‐time quantitative PCR and the 2(‐Delta Delta C(T)) Method" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.J. Livak" 1 => "T.D. Schmittgen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/meth.2001.1262" "Revista" => array:6 [ "tituloSerie" => "Methods." "fecha" => "2001" "volumen" => "25" "paginaInicial" => "402" "paginaFinal" => "408" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846609" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0265" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human skin pigmentation: melanocytes modulate skin color in response to stress" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G.E. Costin" 1 => "V.J. Hearing" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1096/fj.06-6649rev" "Revista" => array:6 [ "tituloSerie" => "FASEB J." "fecha" => "2007" "volumen" => "21" "paginaInicial" => "976" "paginaFinal" => "994" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17242160" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0270" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Melasma, a photoaging disorder" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T. Passeron" 1 => "M. Picardo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/pcmr.12684" "Revista" => array:6 [ "tituloSerie" => "Pigment Cell Melanoma Res." "fecha" => "2018" "volumen" => "31" "paginaInicial" => "461" "paginaFinal" => "465" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29285880" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0275" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cell aging and cellular senescence in skin aging ‐ Recent advances in fibroblast and keratinocyte biology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "F. Gruber" 1 => "C. Kremslehner" 2 => "L. Eckhart" 3 => "E. Tschachler" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.exger.2019.110780" "Revista" => array:5 [ "tituloSerie" => "Exp Gerontol." "fecha" => "2020" "volumen" => "130" "paginaInicial" => "110780" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31794850" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0280" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Senescent fibroblasts drive ageing pigmentation: A potential therapeutic target for senile lentigo" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.E. Yoon" 1 => "Y. Kim" 2 => "S. Kwon" 3 => "M. Kim" 4 => "Y.H. Kim" 5 => "J.-H. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7150/thno.26975" "Revista" => array:6 [ "tituloSerie" => "Theranostics." "fecha" => "2018" "volumen" => "8" "paginaInicial" => "4620" "paginaFinal" => "4632" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30279727" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0285" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Derivation of Ethnically Diverse Human Induced Pluripotent Stem Cell Lines" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.A. Chang" 1 => "M.L. Tomov" 2 => "S.T. Suhr" 3 => "J. Luo" 4 => "Z.T. Olmsted" 5 => "J.L. Paluh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/srep15234" "Revista" => array:5 [ "tituloSerie" => "Sci Rep." "fecha" => "2015" "volumen" => "5" "paginaInicial" => "15234" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26482195" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0290" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aging and chronic sun exposure cause distinct epigenetic changes in human skin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Gronniger" 1 => "B. Weber" 2 => "O. Heil" 3 => "N. Peters" 4 => "F. Stäb" 5 => "H. Wenck" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1371/journal.pgen.1000971" "Revista" => array:5 [ "tituloSerie" => "PLoS Genet." "fecha" => "2010" "volumen" => "6" "paginaInicial" => "e1000971" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20523906" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0295" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gene and protein expression of oestrogen‐beta and progesterone receptors in facial melasma and adjacent healthy skin in women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.A. Tamega" 1 => "H.A. Miot" 2 => "N.P. Moco" 3 => "M.G. Silva" 4 => "M.E.A. Marques" 5 => "L.D.B. Miot" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ics.12186" "Revista" => array:6 [ "tituloSerie" => "Int J Cosmet Sci." "fecha" => "2015" "volumen" => "37" "paginaInicial" => "222" "paginaFinal" => "228" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25439299" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0300" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Campbell" 1 => "E. Emmerson" 2 => "F. Davies" 3 => "S.C. Giliver" 4 => "A. Krust" 5 => "P. Chambon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1084/jem.20100500" "Revista" => array:6 [ "tituloSerie" => "J Exp Med." "fecha" => "2010" "volumen" => "207" "paginaInicial" => "1825" "paginaFinal" => "1833" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20733032" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0305" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved cutaneous wound healing after intraperitoneal injection of alpha‐melanocyte‐stimulating hormone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K.S. Souza" 1 => "T.A. Cantaruti" 2 => "G.M. Azevedo Jr." 3 => "D.A.A. Galdino" 4 => "C.M. Rodrigues" 5 => "R.A. Costa" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/exd.12609" "Revista" => array:6 [ "tituloSerie" => "Exp Dermatol." "fecha" => "2015" "volumen" => "24" "paginaInicial" => "198" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25431356" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0310" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of wound healing by growth factors and cytokines" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Werner" 1 => "R. Grose" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1152/physrev.2003.83.3.835" "Revista" => array:6 [ "tituloSerie" => "Physiol Rev." "fecha" => "2003" "volumen" => "83" "paginaInicial" => "835" "paginaFinal" => "870" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12843410" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0315" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wnt3a inhibits proliferation but promotes melanogenesis of melan‐a cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Guo" 1 => "K. Yang" 2 => "F. Deng" 3 => "Y. Xing" 4 => "Y. Li" 5 => "X. Lian" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3892/ijmm.2012.1028" "Revista" => array:6 [ "tituloSerie" => "Int J Mol Med." "fecha" => "2012" "volumen" => "30" "paginaInicial" => "636" "paginaFinal" => "642" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22710324" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0320" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Wnt inhibitory factor (WIF)‐1 promotes melanogenesis in normal human melanocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.J. Park" 1 => "M. Kim" 2 => "H. Kim" 3 => "S.Y. Park" 4 => "K.-C. Park" 5 => "J.-P. Ortonne" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Pigment Cell Melanoma Res." "fecha" => "2014" "volumen" => "27" "paginaInicial" => "72" "paginaFinal" => "81" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0325" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "News from the endothelin‐3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest‐associated disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N. Bondurand" 1 => "S. Dufour" 2 => "V. Pingault" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Dev Biol." "fecha" => "2018" "volumen" => "444" "paginaInicial" => "S69" "paginaFinal" => "S156" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0330" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Signaling Cascades Activated by UVB in Human Melanocytes Lead to the Increased Expression of Melanocyte Receptors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Terazawa" 1 => "G. Imokawa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Endothelin B Receptor and c‐KIT. Photochem Photobiol." "fecha" => "2018" "volumen" => "94" "paginaInicial" => "421" "paginaFinal" => "431" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0335" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endothelin‐1 and endothelin‐3 induce chemotaxis and replication of pulmonary artery fibroblasts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.J. Peacock" 1 => "K.E. Dawes" 2 => "A. Shock" 3 => "A.J. Gray" 4 => "J.T. Reeves" 5 => "G.J. Laurent" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1165/ajrcmb/7.5.492" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Cell Mol Biol." "fecha" => "1992" "volumen" => "7" "paginaInicial" => "492" "paginaFinal" => "499" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1419025" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0340" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The bright and dark side of extracellular vesicles in the senescence‐associated secretory phenotype" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Wallis" 1 => "H. Mizen" 2 => "C.L. Bishop" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.mad.2020.111263" "Revista" => array:5 [ "tituloSerie" => "Mech Ageing Dev." "fecha" => "2020" "volumen" => "189" "paginaInicial" => "111263" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32461143" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0345" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Skin Pigmentation and Pigmentary Disorders: Focus on Epidermal/Dermal Cross‐Talk" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Bastonini" 1 => "D. Kovacs" 2 => "M. Picardo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.5021/ad.2016.28.3.279" "Revista" => array:6 [ "tituloSerie" => "Ann Dermatol." "fecha" => "2016" "volumen" => "28" "paginaInicial" => "279" "paginaFinal" => "289" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27274625" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0350" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Interplay Between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B. Russo" 1 => "N.C. Brembilla" 2 => "C. Chizzolini" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3389/fimmu.2020.00648" "Revista" => array:5 [ "tituloSerie" => "Front Immunol." "fecha" => "2020" "volumen" => "11" "paginaInicial" => "648" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32477322" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0355" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Senescent dermal fibroblasts enhance stem cell migration through CCL2/CCR2 axis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Ohgo" 1 => "S. Hasegawa" 2 => "Y. Hasebe" 3 => "H. Mizutani" 4 => "S. Nakata" 5 => "H. Akamatsu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/exd.12701" "Revista" => array:6 [ "tituloSerie" => "Exp Dermatol." "fecha" => "2015" "volumen" => "24" "paginaInicial" => "552" "paginaFinal" => "554" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25808810" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0360" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differential expression of inflammatory cytokines and chemokines in lipopolysaccharide‐stimulated melanocytes from lightly and darkly pigmented skin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I. Tam" 1 => "A. Dzierzega-Lecznar" 2 => "K. Stepien" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/exd.13908" "Revista" => array:6 [ "tituloSerie" => "Exp Dermatol." "fecha" => "2019" "volumen" => "28" "paginaInicial" => "551" "paginaFinal" => "560" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30801846" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0365" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "cellular adhesive molecules serving as signalling mediators" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Yulis" 1 => "D.H.M. Kusters" 2 => "A. Nusrat" 3 => "Cadherins:" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Physiol." "fecha" => "2018" "volumen" => "96" "paginaInicial" => "3883" "paginaFinal" => "3898" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0370" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cadherin‐11 is a novel regulator of extracellular matrix synthesis and tissue mechanics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Row" 1 => "Y. Liu" 2 => "S. Alimperti" 3 => "S.K. Agalwal" 4 => "S.T. Andreadis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1242/jcs.183772" "Revista" => array:6 [ "tituloSerie" => "J Cell Sci." "fecha" => "2016" "volumen" => "129" "paginaInicial" => "2950" "paginaFinal" => "2961" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27311482" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0375" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Superoxide dismutase multigene family: a comparison of the CuZn‐SOD (SOD1) Mn‐SOD (SOD2), and EC‐SOD (SOD3) gene structures, evolution, and expression" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "I.N. Zelko" 1 => "T.J. Mariani" 2 => "R.J. Folz" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0891-5849(02)00905-x" "Revista" => array:6 [ "tituloSerie" => "Free Radic Biol Med." "fecha" => "2002" "volumen" => "33" "paginaInicial" => "337" "paginaFinal" => "349" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12126755" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0380" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of oxidative stress in melasma: a prospective study on serum and blood markers of oxidative stress in melasma patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "V. Choubey" 1 => "R. Sarkar" 2 => "V. Garg" 3 => "S. Kaushik" 4 => "S. Ghunawat" 5 => "S. Sonthalia" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Int J Dermatol." "fecha" => "2017" "volumen" => "6" "paginaInicial" => "939" "paginaFinal" => "943" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0385" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of manganese superoxide dismutase in skin aging" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "N. Treiber" 1 => "P. Maity" 2 => "K. Singh" 3 => "F. Ferchiu" 4 => "M. Wlaschek" 5 => "K. Scharffetter-Kochanek" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4161/derm.21819" "Revista" => array:6 [ "tituloSerie" => "Dermatoendocrinol." "fecha" => "2012" "volumen" => "4" "paginaInicial" => "232" "paginaFinal" => "235" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23467724" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0390" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Age‐Associated Increase in Skin Fibroblast‐Derived Prostaglandin E2 Contributes to Reduced Collagen Levels in Elderly Human Skin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Li" 1 => "D. Lei" 2 => "W.R. Swindell" 3 => "W. Xia" 4 => "S. Weng" 5 => "J. Fu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/jid.2015.157" "Revista" => array:6 [ "tituloSerie" => "J Invest Dermatol." 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Morfologia, taxa de crescimento e expressão gênica de fibroblastos no melasma facial

Ana Cláudia Cavalcante Espósitoa, Gabrielli Brianezib, Luciane Donida Bartoli Miota, Hélio Amante Miota,

Corresponding author

heliomiot@gmail.com

Autor para correspondência.

a Departamento de Dermatologia e Radioterapia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil

b Departamento de Patologia, Faculdade de Medicina, Universidade Estadual Paulista, Botucatu, SP, Brasil

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adjacente &#40;fotoexposta&#41;&#44; a pele com melasma apresenta aumento na quantidade de melanina epid&#233;rmica&#44; melanossomas mais maduros&#44; melan&#243;citos hipertrofiados e elastose solar proeminente&#46; Tamb&#233;m h&#225; um aumento no n&#250;mero de vasos e de mast&#243;citos&#44; bem como express&#227;o aumentada de mediadores inflamat&#243;rios&#44; como iNOS&#44; NF&#8208;K&#946;&#44; endotelina&#44; e fatores de crescimento&#44; como VEGF&#44; fator de crescimento derivado de hepat&#243;citos&#44; de <span class="elsevierStyleItalic">stem cell</span>&#44; de fibroblastos e de nervos&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> Melan&#243;citos em p&#234;ndulo &#8211; melan&#243;citos da camada basal que se projetam em dire&#231;&#227;o &#224; derme superior &#8211; e altera&#231;&#245;es na membrana basal tamb&#233;m foram descritos no melasma&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> H&#225; diminui&#231;&#227;o do col&#225;geno tipo&#160;I associada a aumento na atividade de metaloproteinases &#40;MMP&#160;1&#44;&#160;2&#44;&#160;3&#160;e&#160;9&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> Alguns genes relacionados ao metabolismo lip&#237;dico est&#227;o regulados negativamente na pele do melasma e a fun&#231;&#227;o da barreira cut&#226;nea &#233; prejudicada&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">A exposi&#231;&#227;o solar &#233; o principal fator de risco para o desenvolvimento do melasma&#46; A fotoexposi&#231;&#227;o cr&#244;nica&#44; al&#233;m da melanog&#234;nese&#44; induz estresse oxidativo&#44; o que promove senesc&#234;ncia celular&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> Al&#233;m do fotoenvelhecimento e do envelhecimento intr&#237;nseco&#44; o melasma apresenta um fen&#243;tipo senescente mais proeminente na pele acometida&#46; A senesc&#234;ncia celular precoce induzida pela radia&#231;&#227;o ultravioleta &#40;RUV&#41; promove altera&#231;&#245;es funcionais que podem deflagrar e perpetuar a melanog&#234;nese&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Os fibroblastos t&#234;m um papel central na pigmenta&#231;&#227;o&#44; e sua transi&#231;&#227;o para perfil senescente promove modifica&#231;&#227;o de suas atividades aut&#243;crina e par&#225;crina&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> Na pele com melasma&#44; os fibroblastos liberam mais fator derivado de <span class="elsevierStyleItalic">stem cell</span> e seu receptor epid&#233;rmico c&#8208;kit&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a> Fibroblastos senescentes podem expressar fatores inflamat&#243;rios e melanog&#234;nicos&#44; o que pode levar ao desenvolvimento do melasma&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">O fen&#243;tipo senescente foi identificado nos fibroblastos com melasma de maneira mais intensa que na pele adjacente fotoexposta a partir da imunoexpress&#227;o de p16<span class="elsevierStyleSup">INK4A</span>&#44; o que pode justificar o est&#237;mulo para a pigmenta&#231;&#227;o cut&#226;nea sustentada&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">9&#44;10</span></a> Por&#233;m&#44; at&#233; o momento&#44; n&#227;o foi explorado o potencial de replica&#231;&#227;o celular&#44; ou caracterizado o perfil de express&#227;o g&#234;nica desses fibroblastos d&#233;rmicos&#44; no que se refere a fatores de crescimento e reparo tecidual&#44; ativa&#231;&#227;o da via de crescimento tecidual WNT&#47;&#946;&#8208;catenina &#40;WNT&#41;&#44; neocolag&#234;nese&#44; s&#237;ntese de metaloproteinases&#44; receptores de estrog&#234;nios e mecanismos antioxidantes&#46; Tal caracteriza&#231;&#227;o pode subsidiar modelos fisiopatol&#243;gicos e estrat&#233;gias de tratamento&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Este estudo teve como objetivo explorar a morfologia&#44; a taxa de crescimento e o perfil de express&#227;o g&#234;nica de fibroblastos oriundos do melasma facial&#44; em compara&#231;&#227;o com a pele adjacente fotoexposta&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="par0035" class="elsevierStylePara elsevierViewall">Este projeto foi aprovado pelo Conselho de &#201;tica em Pesquisa &#40;Unesp&#44; Botucatu&#8208;SP&#44; n&#46;&#176;&#160;0461&#8208;11&#41; e todos os participantes consentiram em participar&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Dez mulheres adultas com melasma facial foram biopsiadas &#40;<span class="elsevierStyleItalic">punch</span>&#160;2&#160;mm&#44; utilizando t&#233;cnica est&#233;ril&#41; na pele com melasma da regi&#227;o malar e na pele fotoexposta adjacente clinicamente normal &#40;&#60; 2&#160;cm de dist&#226;ncia&#41;&#44; lateralmente&#46; As participantes estavam sem tratamento para a dermatose por pelo menos&#160;30&#160;dias&#44; exceto pelo uso de protetor solar&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Os fragmentos de pele foram seccionados e colocados em cultura de fibroblastos&#44; mantidos em meio&#160;106&#160;&#40;Gibco<span class="elsevierStyleSup">TM</span>&#41; contendo fatores de crescimento &#40;LSGS Kit&#44; Gibco<span class="elsevierStyleSup">TM</span>&#41;&#46; Os fibroblastos foram semeados &#40;em triplicada&#41; a uma densidade de&#160;5&#215;10<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a> em placa de cultura celular de&#160;12&#160;po&#231;os&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Fibroblastos cultivados&#44; de pele s&#227; e lesada&#44; de cinco participantes foram semeados a uma densidade de&#160;1 &#215; 10<span class="elsevierStyleSup">4</span> em placa de cultura celular de&#160;seis&#160;po&#231;os&#44; e o n&#250;mero de c&#233;lulas por cm<span class="elsevierStyleSup">2</span> foi avaliado ap&#243;s&#160;2&#44;&#160;5&#160;e&#160;8&#160;dias&#44; a partir da avalia&#231;&#227;o de&#160;30&#160;campos&#44; e comparados &#40;entre as topografias&#41; por modelo linear generalizado de efeitos mistos&#46; A normalidade das amostras foi avaliada pelo teste de Shapiro&#8208;Wilk&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Posteriormente&#44; a senesc&#234;ncia celular foi avaliada por meio de <span class="elsevierStyleItalic">senescence &#946;&#8208;galactosidase</span> &#40;SA&#8208;&#946;&#8208;gal&#41; <span class="elsevierStyleItalic">staining kit</span> &#40;Cell Signaling Technology&#174;&#41;&#44; seguindo as instru&#231;&#245;es do fabricante&#46; Ap&#243;s&#160;24&#160;horas do plaqueamento das c&#233;lulas&#44; foi removido o meio de cultura&#44; seguiu&#8208;se com lavagem com PBS e adi&#231;&#227;o de solu&#231;&#227;o de fixa&#231;&#227;o por&#160;15&#160;minutos &#224; temperatura ambiente&#46; Ent&#227;o&#44; realizou&#8208;se lavagem com PBS por duas vezes e incuba&#231;&#227;o <span class="elsevierStyleItalic">overnight</span> com solu&#231;&#227;o de &#946;&#8208;galactosidase &#40;Cell Signaling Technology&#174;&#41;&#44; a&#160;37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Ap&#243;s remo&#231;&#227;o da solu&#231;&#227;o&#44; foi adicionado glicerina&#160;70&#37;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Foram contadas&#160;300&#160;c&#233;lulas por amostra&#46; A morfologia dos fibroblastos em cultura e o percentual de c&#233;lulas marcadas com SA&#8208;&#946;&#8208;gal citoplasm&#225;tico foram comparados entre as topografias &#40;melasma e pele s&#227; adjacente&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Fibroblastos da cultura celular prim&#225;ria das outras cinco participantes foram submetidos a <span class="elsevierStyleItalic">real&#8208;time PCR array</span> &#40;placa de&#160;96&#160;po&#231;os&#44; <span class="elsevierStyleItalic">Custom RT</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">Profiler PCR Arrays</span>&#44; Qiagen&#41; para avaliar a express&#227;o de&#160;39&#160;genes associados a fatores de crescimento e reparo tecidual&#44; ativa&#231;&#227;o da via WNT&#44; neocolag&#234;nese&#44; s&#237;ntese de metaloproteinases&#44; receptores de estrog&#234;nios e mecanismos antioxidantes&#46; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; O RNA total foi obtido com <span class="elsevierStyleItalic">RNase mini kit</span> &#40;Qiagen&#41;&#44; e a transcri&#231;&#227;o reversa do RNA foi realizada utilizando <span class="elsevierStyleItalic">RT</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">First Strand Kit for RT&#8208;PCR</span> &#40;Qiagen&#41;&#44; seguindo as instru&#231;&#245;es do fabricante&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">O tamanho do efeito para a express&#227;o g&#234;nica &#40;2<span class="elsevierStyleSup">&#8722;&#916;&#916;Ct</span>&#41; foi estimado pelo <span class="elsevierStyleItalic">fold change</span> &#40;melasma&#47;pele adjacente&#41; para cada participante&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a> Os <span class="elsevierStyleItalic">fold changes</span> foram representadas por sua m&#233;dia e 95&#37;&#160;IC&#44; estimados por&#160;10&#46;000&#160;reamostragens com corre&#231;&#227;o acelerada de vi&#233;s &#40;<span class="elsevierStyleItalic">accelerated bias correction</span> &#8211; BCa&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="par0075" class="elsevierStylePara elsevierViewall">Os principais dados cl&#237;nicos e demogr&#225;ficos dos pacientes estudados est&#227;o dispostos na <a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Em todas as amostras&#44; as culturas de fibroblastos da pele do melasma foram de menor densidade celular&#44; e morfologicamente menos alongados&#44; mais largos&#44; menos fusiformes&#44; al&#233;m de apresentar mais c&#233;lulas marcadas com SA&#8208;&#946;&#8208;gal &#40;superioridade m&#233;dia de&#160;34&#37;&#59; 95&#37;&#160;IC&#160;4&#8208;63&#37;&#59; p &#60; 0&#44;05&#41; do que as culturas oriundas da pele adjacente &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">figs&#46; 1 e 2</a>&#41;&#46; Al&#233;m disso&#44; a taxa de crescimento celular foi menor para as amostras de melasma ap&#243;s oito dias em cultura &#40;p &#60; 0&#44;01&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Foram identificadas altera&#231;&#245;es na express&#227;o g&#234;nica dos fibroblastos isoladas da pele com melasma em compara&#231;&#227;o com aqueles isoladas da pele s&#227; adjacente&#46; Os genes <span class="elsevierStyleItalic">WNT3A&#44; EDN3&#44; ESR2&#44; PTG2&#44; MMP1</span> e <span class="elsevierStyleItalic">SOD2</span> estavam regulados positivamente &#40;<span class="elsevierStyleItalic">up&#8208;regulated</span>&#41;&#59; j&#225; os genes <span class="elsevierStyleItalic">COL4A1&#44; CSF2&#44; DKK3&#44; COL7A1&#44; TIMP4&#44; CCL2</span> e <span class="elsevierStyleItalic">CDH11</span> estavam regulados negativamente &#40;<span class="elsevierStyleItalic">down&#8208;regulated</span>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discuss&#227;o</span><p id="par0090" class="elsevierStylePara elsevierViewall">A melanog&#234;nese &#233; processo complexo mediado por est&#237;mulos par&#225;crinos&#44; aut&#243;crinos e ambientais&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a> As altera&#231;&#245;es fenot&#237;picas evidenciadas na pele com melasma n&#227;o decorrem primariamente ou unicamente de altera&#231;&#227;o epid&#233;rmica&#44; uma vez que diversas altera&#231;&#245;es d&#233;rmicas s&#227;o evidentes na pele acometida em compara&#231;&#227;o com a pele fotoexposta s&#227; adjacente&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">14</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">O fibroblasto &#233; o tipo celular mais comum na derme e&#44; em virtude de sua grande longevidade&#44; acumula danos em seu maquin&#225;rio celular&#44; que podem resultar em altera&#231;&#245;es funcionais e morfol&#243;gicas&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> O envelhecimento intr&#237;nseco e o fotoenvelhecimento est&#227;o associados &#224; diminui&#231;&#227;o no n&#250;mero e na taxa de prolifera&#231;&#227;o de fibroblastos&#59; neste contexto&#44; a compara&#231;&#227;o do perfil g&#234;nico de fibroblastos oriundos da pele com melasma com o de &#225;rea fotoexposta adjacente s&#227; refor&#231;a que as altera&#231;&#245;es g&#234;nicas s&#227;o independentes da idade e da fotoexposi&#231;&#227;o&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3&#44;15</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Considerando a import&#226;ncia dos fibroblastos d&#233;rmicos na regula&#231;&#227;o da pigmenta&#231;&#227;o&#44; as modifica&#231;&#245;es de suas atividades aut&#243;crinas e par&#225;crinas podem influenciar as desordens pigmentares&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> Neste estudo&#44; identificamos perda da morfologia fusiforme&#44; maior quantidade de SA&#8208;&#946;&#8208;gal citoplasm&#225;tico e menor taxa de crescimento nos fibroblastos da pele com melasma&#46; Essas altera&#231;&#245;es morfol&#243;gicas e metab&#243;licas endossam um fen&#243;tipo senescente nos fibroblastos da pele com melasma&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A senesc&#234;ncia &#233; fator central nos mecanismos de envelhecimento&#44; e o fen&#243;tipo secretor associado &#224; senesc&#234;ncia &#40;<span class="elsevierStyleItalic">senescence&#8208;associated secretory phenotype</span> &#8208; SASP&#41; &#233; conhecido por ser o principal desencadeante dos fen&#243;tipos relacionados &#224; idade&#44; como rugas e pigmenta&#231;&#227;o&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> Deve&#8208;se ressaltar que h&#225; evid&#234;ncias sobre diferen&#231;as fenot&#237;picas relacionadas &#224; etnia e suscetibilidade &#224; senesc&#234;ncia de fibroblastos&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Fibroblastos senescentes secretam citocinas inflamat&#243;rias e <span class="elsevierStyleItalic">stem cell factor</span>&#44; que promovem a degrada&#231;&#227;o do col&#225;geno por meio da ativa&#231;&#227;o de MMPs&#44; e t&#234;m potencial mit&#243;tico reduzido&#46; H&#225; aumento da degrada&#231;&#227;o do estroma e comprometimento no reparo tecidual&#44; conforme evidenciado na derme do melasma&#46; Portanto&#44; uma estrutura em mosaico de suscetibilidade tecidual &#224; senesc&#234;ncia pode ser teorizada para o desenvolvimento do melasma em uma pele sob est&#237;mulos ambientais&#44; como radia&#231;&#227;o UV&#44; e horm&#244;nios sexuais&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Houve aumento da express&#227;o g&#234;nica de MMP1 e diminui&#231;&#227;o da express&#227;o dos col&#225;genos&#160;IV&#44; VII &#40;<span class="elsevierStyleItalic">COL4A1</span>&#44; <span class="elsevierStyleItalic">COL7A1</span>&#41; e <span class="elsevierStyleItalic">TIMP4</span> nos fibroblastos isolados da pele com melasma&#46; Durante o processo de senesc&#234;ncia&#44; h&#225; aumento progressivo da produ&#231;&#227;o de metaloproteinase e diminui&#231;&#227;o do processo de reparo&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a> Al&#233;m disso&#44; nos fibroblastos d&#233;rmicos&#44; o &#945;&#8208;MSH promove <span class="elsevierStyleItalic">upregulation</span> da colagenase intersticial e atenua a s&#237;ntese de col&#225;geno induzida por TGF&#946;1&#46; J&#225; os danos &#224; derme superior e &#224; zona da membrana basal facilitam o tr&#226;nsito de fatores melanog&#234;nicos para a camada basal&#46; Neste estudo&#44; apesar de uma implica&#231;&#227;o marginal&#44; <span class="elsevierStyleItalic">MMP9</span> demonstrou uma alta <span class="elsevierStyleItalic">fold change</span> &#40;&#62; 2&#41;&#44; o que&#44; em associa&#231;&#227;o com a express&#227;o mais baixa de <span class="elsevierStyleItalic">TIMP1</span> e 4&#44; sugere participa&#231;&#227;o dos fibroblastos da pele com melasma no reparo deficiente da derme superior e angiog&#234;nese&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">O papel dos horm&#244;nios sexuais na express&#227;o cut&#226;nea do receptor de estr&#243;geno &#946; no melasma est&#225; bem estabelecido&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">19</span></a> Em geral&#44; o <span class="elsevierStyleItalic">ESR2</span> &#233; expresso durante o processo de reparo&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a> A derme superior e a membrana basal est&#227;o muito danificadas na pele com melasma&#44; em compara&#231;&#227;o com a pele fotoexposta adjacente s&#227; e a pele fotoprotegida&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;14</span></a> Al&#233;m disso&#44; o estr&#243;geno&#44; &#945;&#8208;MSH e HGF estimulam a melanog&#234;nese pela liga&#231;&#227;o direta ao receptor do melan&#243;cito e tamb&#233;m s&#227;o liberados durante o processo de cicatriza&#231;&#227;o de feridas&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">21&#44;22</span></a> Esses achados indicam que o processo cr&#244;mico e malsucedido de reparo da derme superior pode induzir melanog&#234;nese no melasma&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Alguns genes relacionados &#224; via Wnt&#47;&#946;&#8208;catenina apresentaram comportamento distinto nos fibroblastos de pele com melasma em rela&#231;&#227;o a pele adjacente fotoexposta&#59; o fator inibit&#243;rio DKK3 apresentou <span class="elsevierStyleItalic">down&#8208;regulation</span>&#44; enquanto WNT3A estava superexpresso&#46; WNT3A desempenha um papel importante no controle da prolifera&#231;&#227;o e diferencia&#231;&#227;o de precursores de melan&#243;citos e angiog&#234;nese&#46; Em melan&#243;citos maduros&#44; o WNT3A aumenta a quantidade de melanina e a atividade da tirosinase&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> A via Wnt est&#225; envolvida na fisiopatologia do melasma&#44; e a diminui&#231;&#227;o da express&#227;o do fator inibit&#243;rio DKK3 nos fibroblastos pode influenciar a ativa&#231;&#227;o epid&#233;rmica de WNT1&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">4</span></a> Al&#233;m disso&#44; WNT3A &#233; importante para o processo de reparo tecidual&#44; podendo ser ativado em decorr&#234;ncia dos danos &#224; derme superior&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">24</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">EDN3 &#233; pept&#237;deo de 21 amino&#225;cidos e ativa preferencialmente EDNRB&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a> A sinaliza&#231;&#227;o de EDN3 &#233; importante no desenvolvimento normal dos melan&#243;citos da epiderme e da coroide&#44; atuando durante a prolifera&#231;&#227;o&#44; diferencia&#231;&#227;o e sobreviv&#234;ncia celular&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a> Queratin&#243;citos expostos ao ultravioleta&#160;B aumentam a produ&#231;&#227;o e a secre&#231;&#227;o de EDN&#44; fazendo com que os melan&#243;citos adjacentes ativem a cascata melanog&#234;nica&#46; Al&#233;m disso&#44; melan&#243;citos expostos a essa mesma radia&#231;&#227;o t&#234;m aumento na express&#227;o de c&#8208;KIT e EDNRB&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a> EDN3 tamb&#233;m participa da quimiotaxia de fibroblastos&#44; independentemente de prolongar a sobreviv&#234;ncia e diferencia&#231;&#227;o celular&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Fibroblastos senescentes est&#227;o associados &#224; defici&#234;ncia nas respostas imunol&#243;gicas e na supress&#227;o tumoral da pele&#44; mas o SASP pode variar entre os tecidos e tipos de est&#237;mulo&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> O CSF participa do crescimento&#44; da diferencia&#231;&#227;o e da sobreviv&#234;ncia dos melan&#243;citos&#44; bem como do recrutamento de c&#233;lulas&#8208;tronco&#46; Queratin&#243;citos expostos &#224; RUV do tipo A <span class="elsevierStyleItalic">in vitro</span> apresentam um n&#237;vel mais elevado de CSF&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">29</span></a> Al&#233;m disso&#44; a IL&#8208;1 produzida por queratin&#243;citos induz fibroblastos a sintetizar CSF&#44; o que promove a prolifera&#231;&#227;o e a diferencia&#231;&#227;o de queratin&#243;citos&#46; Uma diminui&#231;&#227;o de CSF nos fibroblastos senescentes pode configurar redu&#231;&#227;o nos est&#237;mulos aos queratin&#243;citos&#44; o que dificulta o reparo ao tecido danificado&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">CCL2 &#233; quimiocina que atua como regulador cr&#237;tico no recrutamento de macr&#243;fagos e c&#233;lulas&#8208;tronco durante a cicatriza&#231;&#227;o de feridas&#44; no c&#226;ncer e em infec&#231;&#245;es&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a> Ap&#243;s a estimula&#231;&#227;o celular com lipopolissacar&#237;deo&#44; h&#225; uma <span class="elsevierStyleItalic">down&#8208;regulation</span> constitucional de <span class="elsevierStyleItalic">CCL2</span> nos melan&#243;citos de indiv&#237;duos melanod&#233;rmicos em compara&#231;&#227;o com os melan&#243;citos de indiv&#237;duos de fototipo baixo&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> O perfil de express&#227;o de <span class="elsevierStyleItalic">CCL2</span> nos fibroblastos pode induzir o fen&#243;tipo focal mais escuro do melasma&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">As prote&#237;nas da fam&#237;lia das caderinas desempenham papel importante na regula&#231;&#227;o da ades&#227;o intercelular e na s&#237;ntese da matriz extracelular&#44; al&#233;m de contribu&#237;rem para a sinaliza&#231;&#227;o de eventos que controlam a homeostase celular&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a> Nos fibroblastos da pele&#44; CDH11 regula a s&#237;ntese de col&#225;geno e elastina&#44; e sua <span class="elsevierStyleItalic">down&#8208;regulation</span> pode influenciar uma diminui&#231;&#227;o no reparo da derme na pele com melasma&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">A super&#243;xido dismutase &#40;SOD&#41; &#233; parte do sistema antioxidante enzim&#225;tico e &#233; a principal enzima respons&#225;vel pela depura&#231;&#227;o dos radicais livres de oxig&#234;nio&#44; por meio da convers&#227;o de &#226;nions super&#243;xido em per&#243;xido de hidrog&#234;nio e oxig&#234;nio&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a> A SOD &#233; um complexo de enzimas intracelulares&#44; e o n&#237;vel s&#233;rico de SOD &#233; maior entre os pacientes com melasma quando comparados aos controles&#44; o que indica aumento do estado oxidativo sist&#234;mico e refor&#231;a o uso de antioxidantes no tratamento do melasma&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a> SOD2 &#233; uma enzima mitocondrial tetram&#233;rica que cont&#233;m mangan&#234;s e &#233; direcionada ao espa&#231;o intermembrana mitocondrial&#46; O aumento de SOD2 identificado nos fibroblastos &#233; induzido por ambiente de estresse oxidativo e pode ser resultado de m&#250;ltiplas citocinas inflamat&#243;rias&#59; al&#233;m disso&#44; &#233; um fen&#243;tipo caracter&#237;stico em fibroblastos senescentes&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">35&#44;37</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">A c&#233;lula cut&#226;nea que mais cont&#233;m PTGS &#233; o fibroblasto&#46; Essa enzima participa da s&#237;ntese de prostaglandina E2 &#40;PGE2&#41; a partir do &#225;cido araquid&#244;nico&#44; e a PGE2 inibe <span class="elsevierStyleItalic">in vitro</span> a produ&#231;&#227;o de col&#225;geno pelos fibroblastos&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a> A indu&#231;&#227;o de PTGS &#233; not&#225;vel em c&#233;lulas senescentes&#44; que aumentam a libera&#231;&#227;o de PGE2&#44; levando a redu&#231;&#227;o na s&#237;ntese de col&#225;geno tipo&#160;I&#44; vasodilata&#231;&#227;o e quimiotaxia&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a> Al&#233;m disso&#44; o PGE2 pode induzir diretamente a melanog&#234;nese e aumento de dendritos nos melan&#243;citos ap&#243;s irradia&#231;&#227;o com UV&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">39&#44;40</span></a> O fen&#243;tipo pr&#243;&#8208;inflamat&#243;rio dos fibroblastos no melasma pode induzir dano &#224; derme superior e uma melanog&#234;nese sustentada&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Este estudo tem limita&#231;&#245;es relacionadas ao pequeno tamanho amostral e &#224; falta de ensaios prote&#244;micos ou funcionais para confirmar os achados&#46; No entanto&#44; os resultados foram consistentes e permitiram explorar&#44; de modo preliminar&#44; a hip&#243;tese sobre o papel dos fibroblastos na patog&#234;nese do melasma&#44; prospectando novas investiga&#231;&#245;es ligadas &#224; patog&#234;nese e estrat&#233;gias terap&#234;uticas do melasma&#46; A amostra de pacientes submetida ao ensaio de senesc&#234;ncia e de prolifera&#231;&#227;o foi diferente da submetida &#224; compara&#231;&#227;o da express&#227;o g&#234;nica&#44; apesar de os resultados serem paralelos&#46; Finalmente&#44; a investiga&#231;&#227;o de fibroblastos oriundos de controles sem melasma&#44; pareados por idade&#44; padr&#227;o de fotoexposi&#231;&#227;o&#44; fotoenvelhecimento e fototipo&#44; poderia tamb&#233;m elucidar a respeito da suscetibilidade individual dos fibroblastos de portadoras de melasma &#224; senesc&#234;ncia&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Novos estudos devem investigar os fatores regulat&#243;rios dessas vias e a rede de citocinas entre queratin&#243;citos&#44; melan&#243;citos&#44; nervos&#44; endot&#233;lio e fibroblastos no melasma&#44; preferencialmente por meio de estudos com culturas teciduais&#44; para experimentos gen&#244;micos&#44; prote&#244;micos e funcionais&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclus&#245;es</span><p id="par0170" class="elsevierStylePara elsevierViewall">Os fibroblastos da pele com melasma apresentaram menor taxa de crescimento&#44; morfologia menos fusiforme e maior ac&#250;mulo de SA&#8208;&#946;&#8208;gal do que os da pele fotoexposta s&#227; adjacente&#46; Al&#233;m disso&#44; seu perfil de express&#227;o g&#234;nica compreendeu fatores pr&#243;&#8208;inflamat&#243;rios&#44; pr&#243;&#8208;melanog&#234;nicos e relacionados ao d&#233;ficit de reparo tecidual&#44; o que pode induzir dano &#224; derme superior e sustentar o fen&#243;tipo pigmentar focal no melasma&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Financiamento</span><p id="par0175" class="elsevierStylePara elsevierViewall">FAPESP &#8211; n&#176;&#160;2012&#47;09233&#8208;5&#44; 2012&#47;05004&#8208;1&#59; CNPq &#8211; n&#176;&#160;401309&#47;2016&#8208;9&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Contribui&#231;&#227;o dos autores</span><p id="par0180" class="elsevierStylePara elsevierViewall">Ana Cl&#225;udia Cavalcante Esp&#243;sito&#58; Concep&#231;&#227;o e planejamento do estudo&#59; Obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; Reda&#231;&#227;o do artigo&#59; Revis&#227;o cr&#237;tica de literatura&#59; Aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Gabrielli Brianezi&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Luciane Donida Bartoli Miot&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; participa&#231;&#227;o efetiva na orienta&#231;&#227;o da pesquisa&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">H&#233;lio Amante Miot&#58; Concep&#231;&#227;o e planejamento do estudo&#59; obten&#231;&#227;o&#44; an&#225;lise e interpreta&#231;&#227;o dos dados&#59; an&#225;lise estat&#237;stica&#59; reda&#231;&#227;o do artigo&#59; revis&#227;o cr&#237;tica de literatura&#59; revis&#227;o cr&#237;tica do manuscrito&#59; aprova&#231;&#227;o da vers&#227;o final do manuscrito&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflito de interesses</span><p id="par0200" class="elsevierStylePara elsevierViewall">Nenhum&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Fundamentos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">No melasma&#44; al&#233;m da hiperfun&#231;&#227;o melanoc&#237;tica&#44; evidenciam&#8208;se altera&#231;&#245;es na derme superior e&#44; fibroblastos exercem fun&#231;&#227;o central na s&#237;ntese de col&#225;geno e na indu&#231;&#227;o da pigmenta&#231;&#227;o&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objetivo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Explorar a morfologia&#44; a taxa de crescimento e o perfil de express&#227;o g&#234;nica dos fibroblastos da pele com melasma em compara&#231;&#227;o com fibroblastos da pele s&#227; adjacente&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">M&#233;todos</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Dez mulheres com melasma facial foram biopsiadas &#40;les&#227;o e pele s&#227; adjacente&#41;&#44; e os fragmentos foram processados para cultura de fibroblastos&#46; Amostras de cinco participantes foram semeadas para avalia&#231;&#227;o das curvas de crescimento &#40;dias&#160;2&#44;&#160;5&#160;e&#160;8&#41; e senesc&#234;ncia &#40;SA&#8208;&#946;&#8208;gal&#41;&#46; Amostras das demais participantes foram submetidas a <span class="elsevierStyleItalic">real&#8208;time</span> PCR para avaliar comparativamente a express&#227;o de&#160;39&#160;genes&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Fibroblastos das culturas da pele com melasma eram morfologicamente menos fusiformes e tinham uma propor&#231;&#227;o m&#233;dia&#160;34&#37; &#40;95&#37;&#160;IC&#160;4&#8208;63&#37;&#41; maior de c&#233;lulas marcadas com SA&#8208;&#946;&#8208;gal do que os fibroblastos da pele adjacente&#46; A taxa de crescimento celular foi menor para as amostras de melasma ap&#243;s oito dias &#40;p &#60; 0&#44;01&#41;&#46; Os genes <span class="elsevierStyleItalic">WNT3A&#44; EDN3&#44; ESR2&#44; PTG2&#44; MM</span>P1 e <span class="elsevierStyleItalic">SOD2</span> estavam sobreregulados&#59; j&#225; <span class="elsevierStyleItalic">COL4A1&#44; CSF2&#44; DKK3&#44; COL7A1&#44; TIMP4&#44; CCL2</span> e <span class="elsevierStyleItalic">CDH11</span> estavam subregulados nos fibroblastos da pele com melasma em compara&#231;&#227;o com os da pele s&#227; adjacente&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Limita&#231;&#245;es do estudo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Pequeno tamanho amostral&#59; aus&#234;ncia de ensaios funcionais&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclus&#245;es</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Fibroblastos da pele com melasma revelaram menor taxa de crescimento&#44; morfologia menos fusiforme e maior ac&#250;mulo de SA&#8208;&#946;&#8208;gal do que os da pele fotoexposta adjacente&#46; Al&#233;m disso&#44; seu perfil de express&#227;o g&#234;nica compreendeu fatores que podem contribuir para dano &#224; derme superior e melanog&#234;nese sustentada&#46;</p></span>"
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            "detalle" => "Tabela "
            "rol" => "short"
          ]
        ]
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Nome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fun&#231;&#227;o principal &#40;cut&#226;nea&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CCL2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimiocina ligante C&#8208;C tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Quimiocina envolvida no processo de reparo tecidual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CDH11</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caderina 11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relacionada &#224; ades&#227;o celular e reparo epitelial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CDKN2A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidora de quinase dependente de ciclina 2a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta celular ao est&#237;mulo inflamat&#243;rio e neopl&#225;sico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">COL4A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Col&#225;geno tipo IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Componente da membrana basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">COL7A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Col&#225;geno tipo VII&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Componente das fibrilas de ancoragem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CSF2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator estimulador de col&#244;nias tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Envolvida no processo de reparo do epit&#233;lio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DKK1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na relacionada ao Dickkopf 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da via de crescimento celular Wnt&#47;&#946;&#8208;catenina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DKK3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na relacionada ao Dickkopf 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da via de crescimento celular Wnt&#47;&#946;&#8208;catenina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">EDN1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Endotelina tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induz melanog&#234;nese e prolifera&#231;&#227;o vascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">EDN3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Endotelina tipo 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induz melanog&#234;nese e prolifera&#231;&#227;o vascular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ESR1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor de estrog&#234;nio tipo 1 &#40;&#945;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor de estrog&#234;nio ligado &#224; via can&#244;nica&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ESR2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor de estrog&#234;nio tipo 2 &#40;&#946;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Receptor de estrog&#234;nio ligado ao reparo tecidual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">FGF2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator de crescimento de fibroblastos tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reparo do dano tecidual&#44; mit&#243;tico para fibroblastos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">GLB1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Beta&#8208;galactosidase tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gene constitucional&#46; Controle do experimento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HGF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator de crescimento hep&#225;tico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reparo do dano tecidual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">IL1A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleucina 1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta inflamat&#243;ria prim&#225;ria da pele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">IL1B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleucina 1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta inflamat&#243;ria prim&#225;ria da pele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">IL6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interleucina 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta inflamat&#243;ria prim&#225;ria da pele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MAPK14</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na&#8208;quinase ativada por mit&#243;geno 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta celular ao est&#237;mulo inflamat&#243;rio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MIF</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator de inibi&#231;&#227;o da migra&#231;&#227;o de macr&#243;fago&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta inflamat&#243;ria prim&#225;ria da pele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MMP1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metaloproteinase tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degrada&#231;&#227;o dos col&#225;genos tipo I&#44; II e III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MMP2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metaloproteinase tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degrada&#231;&#227;o do col&#225;geno tipo IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MMP7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metaloproteinase tipo 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degrada&#231;&#227;o da matriz extracelular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MMP9</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metaloproteinase tipo 9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degrada&#231;&#227;o da matriz extracelular e angiog&#234;nese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">NGR1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuroregulina tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Regula o crescimento melanoc&#237;tico e cor da pele&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">OXR1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na de resist&#234;ncia oxidativa tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta celular ao estresse oxidativo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">OXSR1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na de estresse oxidativo tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Resposta celular ao estresse oxidativo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">PTGS2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ciclo&#8208;oxigenase tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#237;ntese de prostaglandina E2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SOD1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Super&#243;xido dismutase tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Protege a c&#233;lula das esp&#233;cies ativas de oxig&#234;nio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SOD2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Super&#243;xido dismutase tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induzida em resposta ao estresse oxidativo mitocondrial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TIMP1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da metaloproteinase tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da degrada&#231;&#227;o dos col&#225;genos I&#44; II e III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TIMP2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da metaloproteinase tipo 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da degrada&#231;&#227;o do col&#225;geno IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TIMP3</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da metaloproteinase tipo 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da degrada&#231;&#227;o do col&#225;geno e matriz extracelular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TIMP4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da metaloproteinase tipo 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibidor da degrada&#231;&#227;o da matriz extracelular&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">TP53</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prote&#237;na p53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Marcador de fotoagress&#227;o UVB&#44; antiangiog&#234;nico&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">VEGFA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator de crescimento endotelial tipo A&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Promotor da angiog&#234;nese&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">WIF1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fator inibidor WNT tipo 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inibe a via de crescimento celular Wnt &#47; &#946;&#8208;catenina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">WNT3A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Membro 3A da fam&#237;lia WNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ativador da via can&#244;nica Wnt &#47; &#946;&#8208;catenina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">WNT5A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Membro 5A da fam&#237;lia WNT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ativador da via n&#227;o&#8208;can&#244;nica Wnt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="6" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Curva de crescimento&#44; morfologia e marca&#231;&#227;o SA&#8208;&#946;&#8208;gal</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Idade&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fototipo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tempo de melasma &#40;anos&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hist&#243;ria familiar de melasma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">mMASI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">35&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">III&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">11&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="6" align="left" valign="\n
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                  \t\t\t\t">Teste de express&#227;o g&#234;nica</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sim&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Principais caracter&#237;sticas das dez pacientes com melasma facial submetidas &#224; bi&#243;psia da face na regi&#227;o com melasma malar e pele facial fotoexposta adjacente&#44; cujas amostras foram utilizadas para curva de crescimento&#44; morfologia e marca&#231;&#227;o SA&#8208;&#946;&#8208;gal&#44; ou teste de express&#227;o g&#234;nica</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Refer&#234;ncias"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exploratory Study of Epidermis&#44; Basement Membrane Zone Upper Dermis Alterations and Wnt Pathway Activation in Melasma Compared to Adjacent and Retroauricular Skin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;C&#46;C&#46; Esp&#243;sito"
                            1 => "G&#46; Brianezi"
                            2 => "N&#46;P&#46; Souza"
                            3 => "L&#46;D&#46;B&#46; Miot"
                            4 => "H&#46;A&#46; Miot"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5021/ad.2020.32.2.101"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Dermatol&#46;"
                        "fecha" => "2020"
                        "volumen" => "32"
                        "paginaInicial" => "101"
                        "paginaFinal" => "108"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33911720"
                            "web" => "Medline"
                          ]
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                ]
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            1 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ultrastructural characterization of damage in the basement membrane of facial melasma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;C&#46;C&#46; Esposito"
                            1 => "G&#46; Brianezi"
                            2 => "N&#46;P&#46; De Souza"
                            3 => "D&#46;C&#46; Santos"
                            4 => "L&#46;D&#46;B&#46; Miot"
                            5 => "H&#46;A&#46; Miot"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00403-019-01979-w"
                      "Revista" => array:6 [
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                        "volumen" => "312"
                        "paginaInicial" => "223"
                        "paginaFinal" => "227"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31531731"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of fibroblast&#8208;derived factors in the pathogenesis of melasma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;W&#46; Byun"
                            1 => "I&#46;S&#46; Park"
                            2 => "G&#46;S&#46; Choi"
                            3 => "J&#46; Shin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ced.12874"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Dermatol&#46;"
                        "fecha" => "2016"
                        "volumen" => "41"
                        "paginaInicial" => "601"
                        "paginaFinal" => "609"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27416970"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exploring pathways for sustained melanogenesis in facial melasma&#58; an immunofluorescence study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;C&#46;C&#46; Esposito"
                            1 => "G&#46; Brianezi"
                            2 => "N&#46;P&#46; Souza"
                            3 => "L&#46;D&#46;B&#46; Miot"
                            4 => "H&#46;A&#46; Miot"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/ics.12468"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Cosmet Sci&#46;"
                        "fecha" => "2018"
                        "volumen" => "40"
                        "paginaInicial" => "420"
                        "paginaFinal" => "424"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29846953"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Repeated exposure of human fibroblasts to UVR induces secretion of stem cell factor and senescence"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Shin"
                            1 => "J&#46;H&#46; Kim"
                            2 => "E&#46;K&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1468-3083.2011.04223.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol&#46;"
                        "fecha" => "2012"
                        "volumen" => "26"
                        "paginaInicial" => "1577"
                        "paginaFinal" => "1580"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21929554"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Melasma pathogenesis and influencing factors &#8208; an overview of the latest research"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46; Passeron"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jdv.12049"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol&#46;"
                        "fecha" => "2013"
                        "volumen" => "27"
                        "paginaInicial" => "5"
                        "paginaFinal" => "6"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23205539"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Recent progress in melasma pathogenesis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46;Y&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/pcmr.12404"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pigment Cell Melanoma Res&#46;"
                        "fecha" => "2015"
                        "volumen" => "28"
                        "paginaInicial" => "648"
                        "paginaFinal" => "660"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26230865"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Defective barrier function in melasma skin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46;J&#46; Lee"
                            1 => "J&#46; Lee"
                            2 => "J&#46; Ha"
                            3 => "K&#46;-C&#46; Park"
                            4 => "J&#46;-P&#46; Ortonne"
                            5 => "H&#46;Y&#46; Kang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1468-3083.2011.04337.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Eur Acad Dermatol Venereol&#46;"
                        "fecha" => "2012"
                        "volumen" => "26"
                        "paginaInicial" => "1533"
                        "paginaFinal" => "1537"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22077137"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Senescent fibroblasts in melasma pathophysiology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46; Kim"
                            1 => "S&#46;M&#46; Kim"
                            2 => "S&#46; Kwon"
                            3 => "T&#46;J&#46; Park"
                            4 => "H&#46;Y&#46; Kang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/exd.13814"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Dermatol&#46;"
                        "fecha" => "2019"
                        "volumen" => "28"
                        "paginaInicial" => "719"
                        "paginaFinal" => "722"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30575141"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Premature cell senescence in human skin&#58; Dual face in chronic acquired pigmentary disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "B&#46; Bellei"
                            1 => "M&#46; Picardo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arr.2019.100981"
                      "Revista" => array:5 [
                        "tituloSerie" => "Ageing Res Rev&#46;"
                        "fecha" => "2020"
                        "volumen" => "57"
                        "paginaInicial" => "100981"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31733332"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Kim J&#8208;Y"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "H&#46;Y&#46; Kang"
                            1 => "J&#46;S&#46; Hwang"
                            2 => "J&#46;Y&#46; Lee"
                            3 => "J&#46;H&#46; Ahn"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lee E&#8208;S&#44; et al&#46; The dermal stem cell factor and c&#8208;kit are overexpressed in melasma&#46; Br J Dermatol&#46;"
                        "fecha" => "2006"
                        "volumen" => "154"
                        "paginaInicial" => "1094"
                        "paginaFinal" => "1099"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of relative gene expression data using real&#8208;time quantitative PCR and the 2&#40;&#8208;Delta Delta C&#40;T&#41;&#41; Method"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;J&#46; Livak"
                            1 => "T&#46;D&#46; Schmittgen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1006/meth.2001.1262"
                      "Revista" => array:6 [
                        "tituloSerie" => "Methods&#46;"
                        "fecha" => "2001"
                        "volumen" => "25"
                        "paginaInicial" => "402"
                        "paginaFinal" => "408"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11846609"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human skin pigmentation&#58; melanocytes modulate skin color in response to stress"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46;E&#46; Costin"
                            1 => "V&#46;J&#46; Hearing"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.06-6649rev"
                      "Revista" => array:6 [
                        "tituloSerie" => "FASEB J&#46;"
                        "fecha" => "2007"
                        "volumen" => "21"
                        "paginaInicial" => "976"
                        "paginaFinal" => "994"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17242160"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Melasma&#44; a photoaging disorder"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46; Passeron"
                            1 => "M&#46; Picardo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/pcmr.12684"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pigment Cell Melanoma Res&#46;"
                        "fecha" => "2018"
                        "volumen" => "31"
                        "paginaInicial" => "461"
                        "paginaFinal" => "465"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29285880"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0275"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cell aging and cellular senescence in skin aging &#8208; Recent advances in fibroblast and keratinocyte biology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "F&#46; Gruber"
                            1 => "C&#46; Kremslehner"
                            2 => "L&#46; Eckhart"
                            3 => "E&#46; Tschachler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.exger.2019.110780"
                      "Revista" => array:5 [
                        "tituloSerie" => "Exp Gerontol&#46;"
                        "fecha" => "2020"
                        "volumen" => "130"
                        "paginaInicial" => "110780"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31794850"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Senescent fibroblasts drive ageing pigmentation&#58; A potential therapeutic target for senile lentigo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "Y&#46; Kim"
                            2 => "S&#46; Kwon"
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                            4 => "Y&#46;H&#46; Kim"
                            5 => "J&#46;-H&#46; Kim"
                          ]
                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
                        "tituloSerie" => "Theranostics&#46;"
                        "fecha" => "2018"
                        "volumen" => "8"
                        "paginaInicial" => "4620"
                        "paginaFinal" => "4632"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30279727"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0285"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Derivation of Ethnically Diverse Human Induced Pluripotent Stem Cell Lines"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;A&#46; Chang"
                            1 => "M&#46;L&#46; Tomov"
                            2 => "S&#46;T&#46; Suhr"
                            3 => "J&#46; Luo"
                            4 => "Z&#46;T&#46; Olmsted"
                            5 => "J&#46;L&#46; Paluh"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
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                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Rep&#46;"
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                        "volumen" => "5"
                        "paginaInicial" => "15234"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26482195"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0290"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aging and chronic sun exposure cause distinct epigenetic changes in human skin"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "B&#46; Weber"
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                            4 => "F&#46; St&#228;b"
                            5 => "H&#46; Wenck"
                          ]
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                      "Revista" => array:5 [
                        "tituloSerie" => "PLoS Genet&#46;"
                        "fecha" => "2010"
                        "volumen" => "6"
                        "paginaInicial" => "e1000971"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20523906"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0295"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Gene and protein expression of oestrogen&#8208;beta and progesterone receptors in facial melasma and adjacent healthy skin in women"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
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                            1 => "H&#46;A&#46; Miot"
                            2 => "N&#46;P&#46; Moco"
                            3 => "M&#46;G&#46; Silva"
                            4 => "M&#46;E&#46;A&#46; Marques"
                            5 => "L&#46;D&#46;B&#46; Miot"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Int J Cosmet Sci&#46;"
                        "fecha" => "2015"
                        "volumen" => "37"
                        "paginaInicial" => "222"
                        "paginaFinal" => "228"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25439299"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Campbell"
                            1 => "E&#46; Emmerson"
                            2 => "F&#46; Davies"
                            3 => "S&#46;C&#46; Giliver"
                            4 => "A&#46; Krust"
                            5 => "P&#46; Chambon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1084/jem.20100500"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Exp Med&#46;"
                        "fecha" => "2010"
                        "volumen" => "207"
                        "paginaInicial" => "1825"
                        "paginaFinal" => "1833"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20733032"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0305"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved cutaneous wound healing after intraperitoneal injection of alpha&#8208;melanocyte&#8208;stimulating hormone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "T&#46;A&#46; Cantaruti"
                            2 => "G&#46;M&#46; Azevedo Jr&#46;"
                            3 => "D&#46;A&#46;A&#46; Galdino"
                            4 => "C&#46;M&#46; Rodrigues"
                            5 => "R&#46;A&#46; Costa"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/exd.12609"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Dermatol&#46;"
                        "fecha" => "2015"
                        "volumen" => "24"
                        "paginaInicial" => "198"
                        "paginaFinal" => "203"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25431356"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0310"
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                    0 => array:2 [
                      "titulo" => "Regulation of wound healing by growth factors and cytokines"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Werner"
                            1 => "R&#46; Grose"
                          ]
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                    0 => array:2 [
                      "doi" => "10.1152/physrev.2003.83.3.835"
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                        "tituloSerie" => "Physiol Rev&#46;"
                        "fecha" => "2003"
                        "volumen" => "83"
                        "paginaInicial" => "835"
                        "paginaFinal" => "870"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12843410"
                            "web" => "Medline"
                          ]
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                ]
              ]
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              "identificador" => "bib0315"
              "etiqueta" => "23"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Wnt3a inhibits proliferation but promotes melanogenesis of melan&#8208;a cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Guo"
                            1 => "K&#46; Yang"
                            2 => "F&#46; Deng"
                            3 => "Y&#46; Xing"
                            4 => "Y&#46; Li"
                            5 => "X&#46; Lian"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2012.1028"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Med&#46;"
                        "fecha" => "2012"
                        "volumen" => "30"
                        "paginaInicial" => "636"
                        "paginaFinal" => "642"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22710324"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "24"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Wnt inhibitory factor &#40;WIF&#41;&#8208;1 promotes melanogenesis in normal human melanocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;J&#46; Park"
                            1 => "M&#46; Kim"
                            2 => "H&#46; Kim"
                            3 => "S&#46;Y&#46; Park"
                            4 => "K&#46;-C&#46; Park"
                            5 => "J&#46;-P&#46; Ortonne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Pigment Cell Melanoma Res&#46;"
                        "fecha" => "2014"
                        "volumen" => "27"
                        "paginaInicial" => "72"
                        "paginaFinal" => "81"
                      ]
                    ]
                  ]
                ]
              ]
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            24 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "25"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "News from the endothelin&#8208;3&#47;EDNRB signaling pathway&#58; Role during enteric nervous system development and involvement in neural crest&#8208;associated disorders"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "N&#46; Bondurand"
                            1 => "S&#46; Dufour"
                            2 => "V&#46; Pingault"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Dev Biol&#46;"
                        "fecha" => "2018"
                        "volumen" => "444"
                        "paginaInicial" => "S69"
                        "paginaFinal" => "S156"
                      ]
                    ]
                  ]
                ]
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              "identificador" => "bib0330"
              "etiqueta" => "26"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Signaling Cascades Activated by UVB in Human Melanocytes Lead to the Increased Expression of Melanocyte Receptors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Terazawa"
                            1 => "G&#46; Imokawa"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endothelin B Receptor and c&#8208;KIT&#46; Photochem Photobiol&#46;"
                        "fecha" => "2018"
                        "volumen" => "94"
                        "paginaInicial" => "421"
                        "paginaFinal" => "431"
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                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0335"
              "etiqueta" => "27"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Endothelin&#8208;1 and endothelin&#8208;3 induce chemotaxis and replication of pulmonary artery fibroblasts"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46;J&#46; Peacock"
                            1 => "K&#46;E&#46; Dawes"
                            2 => "A&#46; Shock"
                            3 => "A&#46;J&#46; Gray"
                            4 => "J&#46;T&#46; Reeves"
                            5 => "G&#46;J&#46; Laurent"
                          ]
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Am J Respir Cell Mol Biol&#46;"
                        "fecha" => "1992"
                        "volumen" => "7"
                        "paginaInicial" => "492"
                        "paginaFinal" => "499"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1419025"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0340"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The bright and dark side of extracellular vesicles in the senescence&#8208;associated secretory phenotype"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Wallis"
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                            2 => "C&#46;L&#46; Bishop"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.mad.2020.111263"
                      "Revista" => array:5 [
                        "tituloSerie" => "Mech Ageing Dev&#46;"
                        "fecha" => "2020"
                        "volumen" => "189"
                        "paginaInicial" => "111263"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32461143"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0345"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Skin Pigmentation and Pigmentary Disorders&#58; Focus on Epidermal&#47;Dermal Cross&#8208;Talk"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            1 => "D&#46; Kovacs"
                            2 => "M&#46; Picardo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.5021/ad.2016.28.3.279"
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                        "tituloSerie" => "Ann Dermatol&#46;"
                        "fecha" => "2016"
                        "volumen" => "28"
                        "paginaInicial" => "279"
                        "paginaFinal" => "289"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27274625"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            29 => array:3 [
              "identificador" => "bib0350"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interplay Between Keratinocytes and Fibroblasts&#58; A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "B&#46; Russo"
                            1 => "N&#46;C&#46; Brembilla"
                            2 => "C&#46; Chizzolini"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2020.00648"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol&#46;"
                        "fecha" => "2020"
                        "volumen" => "11"
                        "paginaInicial" => "648"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32477322"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0355"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Senescent dermal fibroblasts enhance stem cell migration through CCL2&#47;CCR2 axis"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Ohgo"
                            1 => "S&#46; Hasegawa"
                            2 => "Y&#46; Hasebe"
                            3 => "H&#46; Mizutani"
                            4 => "S&#46; Nakata"
                            5 => "H&#46; Akamatsu"
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                        ]
                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/exd.12701"
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                        "tituloSerie" => "Exp Dermatol&#46;"
                        "fecha" => "2015"
                        "volumen" => "24"
                        "paginaInicial" => "552"
                        "paginaFinal" => "554"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25808810"
                            "web" => "Medline"
                          ]
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                    ]
                  ]
                ]
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              "identificador" => "bib0360"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Differential expression of inflammatory cytokines and chemokines in lipopolysaccharide&#8208;stimulated melanocytes from lightly and darkly pigmented skin"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/exd.13908"
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                        "tituloSerie" => "Exp Dermatol&#46;"
                        "fecha" => "2019"
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                        "paginaInicial" => "551"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30801846"
                            "web" => "Medline"
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                ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "cellular adhesive molecules serving as signalling mediators"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46; Yulis"
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                            3 => "Cadherins&#58;"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Physiol&#46;"
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                        "paginaInicial" => "3883"
                        "paginaFinal" => "3898"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Cadherin&#8208;11 is a novel regulator of extracellular matrix synthesis and tissue mechanics"
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                          "etal" => false
                          "autores" => array:5 [
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                            2 => "S&#46; Alimperti"
                            3 => "S&#46;K&#46; Agalwal"
                            4 => "S&#46;T&#46; Andreadis"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "J Cell Sci&#46;"
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                        "paginaInicial" => "2950"
                        "paginaFinal" => "2961"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27311482"
                            "web" => "Medline"
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                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Superoxide dismutase multigene family&#58; a comparison of the CuZn&#8208;SOD &#40;SOD1&#41; Mn&#8208;SOD &#40;SOD2&#41;&#44; and EC&#8208;SOD &#40;SOD3&#41; gene structures&#44; evolution&#44; and expression"
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Free Radic Biol Med&#46;"
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                        "volumen" => "33"
                        "paginaInicial" => "337"
                        "paginaFinal" => "349"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12126755"
                            "web" => "Medline"
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                ]
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              "identificador" => "bib0380"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Role of oxidative stress in melasma&#58; a prospective study on serum and blood markers of oxidative stress in melasma patients"
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                        0 => array:2 [
                          "etal" => false
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                            4 => "S&#46; Ghunawat"
                            5 => "S&#46; Sonthalia"
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Dermatol&#46;"
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                        "paginaInicial" => "939"
                        "paginaFinal" => "943"
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                    ]
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              "identificador" => "bib0385"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "The role of manganese superoxide dismutase in skin aging"
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                          "etal" => false
                          "autores" => array:6 [
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                            2 => "K&#46; Singh"
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                            4 => "M&#46; Wlaschek"
                            5 => "K&#46; Scharffetter-Kochanek"
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                        "tituloSerie" => "Dermatoendocrinol&#46;"
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                        "volumen" => "4"
                        "paginaInicial" => "232"
                        "paginaFinal" => "235"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23467724"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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                    0 => array:2 [
                      "titulo" => "Age&#8208;Associated Increase in Skin Fibroblast&#8208;Derived Prostaglandin E2 Contributes to Reduced Collagen Levels in Elderly Human Skin"
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                          "etal" => true
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                            4 => "S&#46; Weng"
                            5 => "J&#46; Fu"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "paginaFinal" => "2188"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25905589"
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                ]
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                      "titulo" => "Roles of inflammation factors in melanogenesis &#40;Review&#41;"
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                          "autores" => array:6 [
                            0 => "C&#46; Fu"
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                            3 => "L&#46; Yi"
                            4 => "X&#46; Tong"
                            5 => "L&#46; Kang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "Mol Med Rep&#46;"
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Article information

ISSN: 26662752
Original language: Portuguese

DOI:10.1016/j.abdp.2022.07.012

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