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O líquen plano é uma condição autoimune mucocutânea que frequentemente afeta a cavidade bucal. O líquen plano oral pode apresentar variadas manifestações clínicas e quando se apresenta na forma erosiva ou ulcerada causa considerável dor e desconforto ao paciente. Existem inúmeras opções terapêuticas disponíveis, dentre elas o uso de imunomoduladores esteroidais e não esteroidais de uso tópico ou sistêmico. O objetivo deste estudo foi realizar uma revisão sistemática da literatura sobre a eficácia e segurança do uso de imunomoduladores não esteroidais tópicos no tratamento do líquen plano oral. As bases de dados consultadas foram o Pubmed e o Embase utilizando-se uma estratégia de busca delineada para este fim. Foram recuperados 1052 artigos após a exclusão das referências duplicadas. Após análise de títulos e resumos, 72 estudos foram selecionados para análise do texto completo. Apenas ensaios clínicos randomizados foram incluídos, resultando em um total de 28 estudos incluídos na revisão sistemática. Os estudos foram sub-divididos de acordo com os fármacos utilizados. Para cada estudo foram extraídos dados qualitativos e quantitativos. Concomitantemente à extração de dados, os artigos foram avaliados quanto ao seu risco de viés. A maioria dos ensaios não observou eficácia diferente quando compararam uso de tacrolimus 0,1% com propionato de clobetasol 0,05% (4 de 6 estudos) ou triancinolona acetonida 0.1% (4 de 5 estudos). Tanto tacrolimus quanto pimecrolimus foram superiores ao placebo. 50% dos estudos encontrados (2/4) mostraram superioridade do tratamento com pimecrolimus em relação à triancinolona acetonida. O uso de ciclosporina foi avaliado em 5 estudos e quando comparada com triancinolona acetonida não foram observadas diferenças significativa em relação à redução de sinais clínicos e sintomas ao final do tratamento, nem em comparação ao propionato de clobetasol, porém este último foi mais eficaz na manutenção da remissão dos sintomas no acompanhamento em um estudo. Foi encontrado apenas um ensaio clínico randomizado para análise de talidomida e de retinoides no tratamento do líquen plano oral. Em ambos estudos não houve diferença na eficácia destes imunomoduladores com corticosteroides tópicos. Nenhum efeito adverso grave foi reportado. Ciclosporina apresentou maior frequência e variedade de efeitos adversos. Em conclusão, esta revisão sistemática da literatura detectou que os imunomoduladores não esteroidais tacrolimus e pimecrolimus são alternativas eficazes e seguras no tratamento do líquen plano oral. Dentre estes, o tacrolimus é a primeira opção pois apresenta maior evidência cientifica disponível até o momento Lichen planus is a mucocutaneous autoimmune condition that often affects the oral cavity. Oral lichen planus (OLP) may present a variety of clinical manifestations. When presented as erosive or ulcerated form can cause considerable pain and discomfort for patients. There are numerous therapeutic options available, including the use of topical or systemic steroidal and non-steroidal immunomodulators. The aim of this study was to conduct a systematic literature review on the efficacy and safety of topical non-steroidal immunomodulators for OLP treatment. The Pubmed and Embase databases were consulted using a search strategy designed for this purpose. 1052 articles were retrieved after excluding duplicate references. After analysis of titles and abstracts, 72 studies were selected for full-text analysis. Only randomized controlled clinical trials were included, resulting in a total of 28 studies included in this systematic review. The studies were subdivided according to the drugs assessed. For each study, qualitative and quantitative data were extracted. Articles were also evaluated for their risk of bias. Most trials did not observe different efficacy when comparing use of 0,1% tacrolimus with 0,05% clobetasol propionate (4 of 6 studies) or 0,1% triamcinolone acetonide (4 of 5 studies). Both tacrolimus and pimecrolimus were superior to placebo. 50% of the studies (2/4) showed superiority of pimecrolimus treatment over triamcinolone acetonide. Cyclosporine was evaluated in 5 studies and when compared with triamcinolone acetonide no significant differences were observed regarding clinical signs and symptoms reduction at the end of treatment. When compared to clobetasol propionate, did not showed difference at end of treatment, however it was more effective in symptom remission maintenance at follow-up in one study. Only one randomized clinical trial was found for thalidomide and retinoid analysis in OLP treatment. There was no difference in the efficacy of these immunomodulators compared to topical corticosteroid. No serious adverse effects have been reported. Cyclosporine had a higher frequency and variety of adverse effects. In conclusion, this systematic literature review has detected that tacrolimus and pimecrolimus non-steroidal immunomodulators are safe and effective alternatives for OLP treatment. Of these, tacrolimus is the first option because it has more scientific evidence available to date

Se efectúa una revisión de las características fisicoquímicas, farmacológicas, toxicológicas y farmacocinéticas de la isotretinoína, retinoide utilizado en el tratamiento de algunos tipos de acné. También se abordan las ventajas e inconvenientes de su uso en terapéutica, además de posibles precauciones, controversias y contraindicaciones de la misma.

Submitted by Helena Bejio (helena.bejio@unioeste.br) on 2020-06-19T18:40:45Z No. of bitstreams: 2 VaneilaTese Final Impressao_Final.pdf: 1718046 bytes, checksum: d303000b157a76b690c3cd5c76e87a78 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Made available in DSpace on 2020-06-19T18:40:45Z (GMT). No. of bitstreams: 2 VaneilaTese Final Impressao_Final.pdf: 1718046 bytes, checksum: d303000b157a76b690c3cd5c76e87a78 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2019-12-13 In this work, two experiments have been carried out. In the first one, the influence of vitamin A on performance, carcass and organ yields, blood parameters, protein and fat deposition, meat quality and bone parameters of broilers were evaluated. 2,300 chicks were distributed in a 2x2x5 factorial scheme, with two lipid sources (soy and palm), two supplementation periods, five levels of vitamin A (0; 3,000; 6,000; 12,000; 24,000 IU kg-1) and 10 repetitions with 23 birds each one. At 22 days old, treatments were redistributed; five repetitions continued to receive the initial diet and five repetitions received a diet supplemented with 6,700 IU kg-1. At 21 days old, the lipid source influenced the feed consumption, feed conversion and abdominal fat. The vitamin A influenced feed intake and weight gain (quadratic response). Vitamin A also influenced the weight of the liver, proventricle and abdominal fat at 21 days old. At 42 days old, the lipid source and vitamin A level influenced feed intake. Weight gain and feed conversion were influenced by period of supplementation and vitamin A level. Carcass yield and meat pH were influenced by vitamin A supplementation. From 1 to 21 days old, vitamin A supplementation was estimated at 15,585 IU kg-1 and at 42 days, 15,527 IU kg-1 and 15,148 IU kg-1 were estimated for periods 1 to 21 and 1 to 42 days, respectively. The second experiment evaluated the influence of vitamin A on performance, carcass and organ yields, bone and skin characteristics, meat quality and myopathies in broilers. 1,920 birds were distributed in a randomized design, with 6 vitamin A supplementations (0; 6,000; 16,000; 26,000; 36,000 and 46,000 IU kg-1), into 16 repetitions with 20 birds. In the period from 22 to 42 days old, treatments were divided, 8 repetitions continued in the initial treatment and 8 repetitions with diets without vitamin A (0 IU kg-1). The level of vitamin A influenced feed intake, weight gain and weight of the proventricle at 21 days old (quadratic response). At 42 days, vitamin A influenced the weight gain and feed intake of birds not supplemented after 21 days. In birds supplemented up to 42 days, weight gain, feed intake and feed conversion obtained quadratic responses. There was an influence of vitamin A on the weight of the wings, chest, legs, small intestine, pancreas, gizzard, abdominal fat, Seedor index, bone rupture strength and yellow intensity (b *). The incidence of WB with higher scores was found in birds supplemented from 5 to 42 days. WS showed a quadratic response to vitamin A supplementation. At 21 days old, supplementation of 28,209 IU kg-1 was estimated, while birds supplemented up to 42 days supplementation of 29,375 IU kg-1 and 27,775 IU kg-1 of vitamin A showed better results for weight gain and feed conversion, respectively. Neste trabalho, foram realizados dois experimentos. No primeiro, avaliou-se a influência da vitamina A no desempenho, rendimento de carcaça e órgãos, parâmetros sanguíneos, deposição de proteína e gordura, qualidade de carne e parâmetros ósseos de frangos de corte. Foram distribuídos 2.300 pintainhos em esquema fatorial 2x2x5, com duas fontes lipídicas (soja e palma), dois tempos de suplementação, cinco níveis de vitamina A (0; 3.000; 6.000; 12.000; 24.000 UI kg-1) e 10 repetições com 23 aves. Aos 22 dias de idade, os tratamentos foram redistribuídos, das 10 repetições, cinco repetições continuaram a receber a dieta inicial e as cinco repetições restantes receberam dieta suplementada com 6.700 UI kg-1. Aos 21 dias de idade, a fonte lipídica influenciou o consumo de ração, conversão alimentar e gordura abdominal. A vitamina influenciou o consumo de ração e ganho de peso (resposta quadrática). A vitamina A influenciou o peso do fígado, proventrículo e gordura abdominal aos 21 dias de idade. Aos 42 dias de idade, a fonte lipídica e o nível de vitamina A influenciaram o consumo de ração. O ganho de peso e a conversão alimentar foram influenciados pelo tempo e nível de vitamina A. O rendimento de carcaça e o pH da carne foram influenciados pela suplementação de vitamina A. De 1 a 21 dias de idade, estimou-se uma suplementação de vitamina A de 15.585 UI kg-1 e aos 42 dias foram estimados 15.527 UI kg-1 e 15.148 UI kg-1 para o períodos 1 a 21 e 1 a 42 dias, respectivamente. O segundo estudo avaliou a influência da vitamina A no desempenho, rendimento de carcaça e órgãos, características ósseas e de pele, qualidade da carne e miopatias em frangos de corte. Foram distribuídas 1.920 aves em delineamento casualizado, com 6 suplementações de vitamina A (0; 6.000; 16.000; 26.000;36.000 e 46.000 UI kg-1), 16 repetições com 20 aves. No período de 22 a 42 dias, os tratamentos foram divididos, 8 repetições continuaram no tratamento inicial e 8 repetições com dietas sem vitamina A (0 UI kg-1). O nível de vitamina A influenciou o consumo de ração, o ganho de peso e peso do proventrículo aos 21 dias de idade (resposta quadrática). Aos 42 dias, a vitamina A influenciou o ganho de peso e o consumo de ração das aves não suplementadas a partir dos 21 dias. Nas aves suplementadas até 42 dias, o ganho de peso, consumo de ração e conversão alimentar obtiveram respostas quadráticas. Houve influência da vitamina A no peso das asas, peito, pernas, intestino delgado, pâncreas, moela, gordura abdominal, índice de Seedor, força de ruptura óssea e intensidade de amarelo (b*). A incidência de WB com maiores escores foi encontrada nas aves suplementadas de 5 a 42 dias. O WS apresentou resposta quadrática à suplementação vitamínica. Foram estimadas as suplementações de 28.209 UI kg-1 aos 21 dias de idade, enquanto aos 42 dias de idade nas aves suplementadas até os 42 dias para ganho de peso a suplementação de 29.375 UI kg-1, e conversão alimentar com 27.775 UI kg-1 de vitamina A apresentam melhores resultados.

Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled at large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that a fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.

In chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival, and expansion. However, the nature of the stromal cells and molecular pathways involved remain largely unknown. Here, we demonstrate that leukemic B lymphocytes induce the activation of retinoid acid synthesis and signaling in the microenvironment. Inhibition of RA-signaling in stromal cells causes deregulation of genes associated with adhesion, tissue organization and chemokine secretion including the B-cell chemokine CXCL13. Notably, reducing retinoic acid precursors from the diet or inhibiting RA-signaling through retinoid-antagonist therapy prolong survival by preventing dissemination of leukemia cells into lymphoid tissues. Furthermore, mouse and human leukemia cells could be distinguished from normal B-cells by their increased expression of Rarγ2 and RXRα, respectively. These findings establish a role for retinoids in murine CLL pathogenesis, and provide new therapeutic strategies to target the microenvironment and to control disease progression., The stromal microenvironment plays a key role in the expansion of chronic lymphocytic leukemia. Here, the authors use the Eµ-TCL1 mouse model to show that leukemic B-cells induce the activation of retinoic acid synthesis in stromal cells of the lymphoid microenvironment, and that impacting on retinoic acid signalling via diet or chemical inhibition prolonged survival by preventing leukemia dissemination and accumulation in lymphoid tissues.

As vitaminas são indispensáveis em diversos processos biológicos, tornando-se crucial para o funcionamento do organismo humano. Devido seu potencial, diversas vitaminas são utilizadas para o desenvolvimento de cosmecêuticos. A Vitamina A foi o primeiro retinoide a ser estudado na área clínica, por sua importância na queretinização e diferenciação epitelial. Esta Revisão de Literatura tem o intuito de avaliar o aperfeiçoamento da molécula de vitamina A nos últimos 30 anos e a aplicação deste componente em formulações cosmecêuticas. Atualmente, os retinoides são uma das classes mais prescritas em dermatologia para preparações cosmeceuticas. São substâncias derivadas da Vitamina A, que de acordo com a literatura, possuem ação principalmente no tratamento de envelhecimento cutâneo, acne e fotoenvelhecimento. Observou-se uma série de inconvenientes associados a utilização de retinoides, como a instabilidade da molécula, os efeitos colaterais e o grande potencial teratogênico, dando início às pesquisas com objetivo de obtenção de um composto menos tóxico e com menores reações adversas. O primeiro composto utilizado foi o retinol, a forma ácida da Vitamina A, porém, um grande número de retinoides foram sintetizados ao longo dos anos, podendo ser caracterizados como de primeira, segunda e terceira geração. A mais recente molécula desenvolvida foi o retinoato de hidroxipinacolona, queapresenta menor irritação da pele, menor instabilidade fotoquímica e toxicidade. Contudo, apesar dos avanços, os retinoides continuam foto instáveis, com potencial teratogênico e irritativo para a pele, não sendo, portanto, substâncias totalmente seguras para o uso.

Reporter analyses of Hox1 and Brachyury (Bra) genes have revealed examples of redundant enhancers that provide regulatory robustness. Retinoic acid (RA) activates through an RA-response element the transcription of Hox1 in the nerve cord of the ascidian Ciona intestinalis. We also found a weak RA-independent neural enhancer within the second intron of Hox1. The Hox1 gene in the larvacean Oikopleura dioica is also expressed in the nerve cord. The O. dioica genome, however, does not contain the RA receptor-encoding gene, and the expression of Hox1 has become independent of RA. We have found that the upstream sequence of the O. dioica Hox1 was able to activate reporter gene expression in the nerve cord of the C. intestinalis embryo, suggesting that an RA-independent regulatory system in the nerve cord might be common in larvaceans and ascidians. This RA-independent redundant regulatory system may have facilitated the Oikopleura ancestor losing RA signaling without an apparent impact on Hox1 expression domains. On the other hand, vertebrate Bra is expressed in the ventral mesoderm and notochord, whereas its ascidian ortholog is exclusively expressed in the notochord. Fibroblast growth factor (FGF) induces Bra in the ventral mesoderm in vertebrates, whereas it induces Bra in the notochord in ascidians. Disruption of the FGF signal does not completely silence Bra expression in ascidians, suggesting that FGF-dependent and independent enhancers might comprise a redundant regulatory system in ascidians. The existence of redundant enhancers, therefore, provides regulatory robustness that may facilitate the acquisition of new expression domains.

La inflamación y la hiperplasia sinovial de la artritis reumatoide (AR) son claves en la progresión del daño articular. Los nuevos tratamientos actuales han mejorado el pronóstico de la AR, pero alrededor de un 30% de pacientes no responde adecuadamente a las nuevas terapias. Por lo tanto, todavía es necesario desarrollar nuevas estrategias terapéuticas. Distintas evidencias indican que los retinoides y la proteína CRABP2 podrían tener un papel en la patogenia de la AR. En este trabajo se demuestra la regulación no convencional e idiosincrática de los retinoides en los sinoviocitos de pacientes con AR. El retinoide ATRA no tuvo un efecto anti-proliferativo, ni pro-apoptótico, como se esperaba. Sin embargo, el retinoide redujo el fenotipo agresivo de los sinoviocitos y moduló su respuesta inflamatoria. Por otro lado, el transportador de retinoides parece contribuir a la resistencia de los sinoviocitos reumatoides a la apoptosis. El silenciamiento de CRABP2 sensibiliza a la apoptosis inducida por Fas. En el modelo de artritis inducida por transferencia de suero K/BxN, la ausencia del crabp2 no modifica la severidad de la artritis y el tratamiento con ATRA agravó la enfermedad, a nivel clínico e histológico.

Resumen Pitiriasis rubra pilaris es una dermatosis eritematoescamosa infrecuente, de etiología desconocida producida por una alteración en la queratinización de la epidermis. Presenta una distribución bimodal con mayor incidencia en la primera y sexta década de vida. Posee una clínica heterogénea clasificada en 6 subtipos según Griffiths, de acuerdo a su presentación clínica y pronóstico. Sus principales hallazgos son pápulas hiperqueratósicas foliculares, queratodermia palmoplantar y placas eritematoesmamosas rojo-anaranjadas que pueden progresar a eritrodermia, con islas de piel sana. En niños las manifestaciones clínicas más frecuentes son la III y IV de la clasificación de Griffiths, según distintos estudios. La histología no es específica pero apoya el diagnóstico. Existen múltiples opciones terapéuticas según la extensión y severidad del cuadro. Presentamos el caso de un preescolar de 5 años de edad con diagnóstico de PRP atípica asociado a eritema extenso, con buena respuesta a corticoides sistémicos y posteriormente a retinoides tópicos. Summary Pityriasis rubra pilaris (PRP) is an unusual erythematous squamous dermatosis of unknown etiology, caused by an alteration of keratinization in the epidermis. This disease presents a bimodal distribution, being its incidence greater in the first and sixth decade of life. It has a heterogeneous clinical manifestation, and, according to Griffiths, has been classified into 6 subtypes, based on clinical features and prognosis. The typical manifestations of this disease are follicular hyperkeratotic papules, palmoplantar keratoderma and orange-red scaly plaques that can progress to erythroderma, with islands of sparing. According to different studies, the most frequent clinical manifestations in children are type III and IV according to Griffiths classification. Histology is not specific but supports diagnosis. There are multiple therapeutic options, depending on the extension and severity of the disorder. This review presents the case of a 5-year- old child case with a diagnosis of atypical PRP associated with extensive erythema, his response to treatment of systemic corticosteroids and later to topical retinoids being good.

Congenital diaphragmatic cupola hernia (CDH) is a developmental abnormality of the diaphragm occurring during embryogenesis, which allows communication between the peritoneal and pleural cavities to persist. In its most frequent form, it affects the posterolateral region of the left diaphragmatic dome (85% of cases). It allows intrathoracic migration of abdominal viscera and impairs the inspiratory efficiency of fetal diaphragmatic movements. The result is a compression of the thoracic viscera which results essentially in pulmonary hypoplasia, a defect in alveolar maturation and pulmonary arterial hypertension (PAH), which causes significant difficulties in neonatal adaptation. Perinatal mortality is high (about 50%, including pregnancy termination and foetal loss) and morbidity remains high among surviving children. For the most severe isolated forms, antenatal care is offered by performing a temporary tracheal occlusion (TO) by endoscopic means to improve pulmonary growth. This procedure is accompanied by an acceleration of pulmonary maturation, observed in animal models, with a decrease in the rate of type II pneumocytes (PII), cells secreting pulmonary surfactant. The deleterious effect of OT can be partially corrected by tracheal disocclusion before birth and/or by steroid administration. Administration of retinoids may also influence pulmonary differentiation and improve the fetal prognosis after OT for CDH. Work in mouse models has established a link between retinoids and HCD, particularly in the nitrofen model, a herbicide that interrupts the retinoid signalling pathway. It has been shown that disruption of the retinoid metabolic pathway can lead to the formation of HCD in the foetus. Retinol or AR supplementation at key times in lung development reduced the incidence of HCD. Maternal AR supplementation can correct lung maturation abnormalities in surgically created HCD in rabbit fetuses. The involvement of the retinoid signalling pathway in the pathophysiology of CDH has been confirmed in humans and in fetuses or neonates with CDH. We have studied the effects of AR administration directly into the foetal trachea, as close to the lung as possible, in addition to EO. In order to be able to deliver AR, it was necessary to find a vehicle for this lipophilic molecule to be instilled in an aqueous medium. Using a rabbit fetus model with a healthy lung, we studied two possible vehicles, liposomes and Miglyol® . We were able to confirm that EO, whatever the molecule injected into the trachea, can increase lung volume and modify the anatomy of the airways by increasing the CRA. The production of SP-B, the surfactant protein, was preserved with the addition of AR, whereas it was decreased when saline was administered. This effect appeared to be more pronounced when AR was coupled to liposomes. Liposomes were therefore chosen as a vehicle to study the effects of intratracheal injection of AR coupled with EO on the rabbit surgical model of HDC. Our results showed that the administration of RA appeared to decrease the apoptosis phenomenon, potentiated the effect of EO on the expression of EDNRA, a reflection of PAH, and normalized the production of surfactant proteins, which is decreased in case of EO. In conclusion, the intratracheal administration of RA at the same time as EO could improve pulmonary vascularisation and maturation.; La hernie de coupole diaphragmatique (HCD) congénitale est une anomalie de développement du diaphragme survenant au cours de l’embryogénèse, qui laisse persister une communication entre les cavités péritonéale et pleurale. Dans sa forme la plus fréquente, elle concerne la région postérolatérale de la coupole diaphragmatique gauche (85% des cas). Elle rend possible la migration intrathoracique de viscères abdominaux et nuit à l’efficacité inspiratoire des mouvements diaphragmatiques foetaux. Il en résulte une compression des viscères thoraciques qui se solde essentiellement par une hypoplasie pulmonaire, un défaut de maturation alvéolaire et une hypertension artérielle pulmonaire (HTAP), à l’origine de difficultés importantes d’adaptation néonatale. La mortalité périnatale est élevée (environ 50%, comprenant les interruptions de grossesses et les pertes foetales) et la morbidité reste importante chez les enfants survivants. Pour les formes isolées les plus sévères, une prise en charge anténatale est proposée par réalisation d’une occlusion temporaire de la trachée (OT) par voie endoscopique permettant une amélioration de la croissance pulmonaire. Ce geste s’accompagne d’une accélération de la maturation pulmonaire, observée sur modèles animaux, avec une diminution du taux de pneumocytes de type II (PII), cellules sécrétrices de surfactant pulmonaire. L’effet délétère de l’OT peut être partiellement corrigé par une désocclusion trachéale avant la naissance et/ou par l’administration de stéroïdes. L’administration de rétinoïdes pourrait aussi influencer la différenciation pulmonaire et améliorer le pronostic fœtal après OT pour HCD. Des travaux menés sur les modèles murins ont permis d’établir un lien entre rétinoïdes et HCD, notamment dans le modèle nitrofène, herbicide qui interrompt la voie de signalisation des rétinoides. Il a été montré qu’une perturbation de la voie métabolique des rétinoïdes pouvait entraîner la formation de HCD chez le foetus. La supplémentation en rétinol ou en AR aux instants clés du développement pulmonaire permettait d’en réduire l’incidence. Une supplémentation maternelle en AR permet de corriger les anomalies de maturation pulmonaire présentes dans les HCD créées chirurgicalement chez des fœtus lapins. L’implication de la voie de signalisation des rétinoïdes dans la physiopathologie de la HCD a été confirmée chez l’homme et chez les fœtus ou nouveau-nés présentant une HCD. Nous avons étudié les effets d’une administration d’AR directement dans la trachée foetale, au plus près du poumon, en complément de l’OT. Afin de pouvoir délivrer de l’AR en intra-trachéal, il était nécessaire de trouver un véhicule pour cette molécule lipophile à instiller en milieu aqueux. En utilisant un modèle de fœtus lapin à poumon sain, nous avons étudié deux véhicules possibles, les liposomes et le Miglyol® . Nous avons pu confirmer que l’OT, quelque soit la molécule injectée dans la trachée, permettait d’augmenter le volume pulmonaire et de modifier l’anatomie des voies aériennes en augmentant le CRA. La production de SP-B, protéine du surfactant, était conservée avec l’adjonction d’AR alors qu’elle était diminuée lorsque du sérum physiologique était administré. Cet effet semblait plus marqué lorsque l’AR était couplé aux liposomes. Les liposomes ont donc été choisis comme véhicule pour étudier les effets de l’injection intratrachéale d’AR couplée à l’OT sur le modèle chirurgical lapin de HDC. Nos résultats montraient que l’administration d’AR semblait diminuer le phénomène d’apoptose, potentialisait l’effet de l’OT sur l’expression d’EDNRA, reflet d’HTAP, et normalisait la production des protéines du surfactant, diminuée en cas d’OT. En conclusion, l’administration intratrachéale d’AR en même temps que l’OT pourrait améliorer la vascularisation et la maturation pulmonaires.

Vitamin A and its active derivates (retinoids) are essential molecules for life from the embryonic development to the adulthood. Because of these numerous functions and especially because of their pro-healing properties, they are commonly used in clinic in dermatology and ophthalmology in particular. Despite this routine clinical use, the molecular and cellular mechanisms used by retinoids to promote a healing process remain unclear. To better understand these mechanisms, but also to expand its clinical use to the premature rupture of fetal membranes (PROM), we looked to pro-healing properties of atRA (active derivative of vitamin A) on the human fetal membranes. While amnion and chorion are unable to initiate a physiological process of healing after injury, our results demonstrate a positive effect of atRA on the migration of primary amniocytes, leading to an healing improvement of up to 80% in vitro. This work, completed by a transcriptomic analysis performed on fetal membranes and primary amniocytes treated or not with atRA, allowed the identification of many genes regulated by atRA within the amnion and the amniocytes. Among these genes, we looked to a member of the lysyl oxidase family, LOXL4, which plays a key role in the dynamic of the extracellular matrix by regulating collagen crosslinking. First, transcription and promotology experiments have shown that atRA strongly induced the expression of LOXL4 in a direct manner. Then, the inhibition of the LOXL4 protein in scratch assay experiments (using β-aminopropionitrile or a specific siRNA) allowed us to demonstrate that the pro-healing effect of atRA was mediated, at least in part, by the retinoid-induction of this gene. Besides providing new elements to understand how atRA exerts their pro-healing properties, this work proposes atRA as a promising candidate to improve the clinical management of premature rupture of the fetal membranes by promoting re-epithelialization of the amnion., La vitamine A et ses dérivés actifs (les rétinoïdes) sont des molécules essentielles à la vie et ce dès la période embryonnaire. Molécules de choix dans de nombreuses applications thérapeutiques, notamment dans les domaines de la dermatologie et de l’ophtalmologie, elles sont le plus couramment utilisées pour leurs propriétés pro-cicatrisantes. Malgré cette utilisation courante en clinique, les mécanismes cellulaires et moléculaires permettant aux rétinoïdes de promouvoir un processus de cicatrisation restent encore mal connus. Afin de mieux appréhender ces mécanismes, mais aussi afin d’élargir leur utilisation clinique à la rupture prématurée des membranes (RPM), je me suis intéressée aux propriétés pro-cicatrisantes de l’atRA (l’un des dérivés actifs de la vitamine A) sur les membranes fœtales. Alors que l’amnios et le chorion sont physiologiquement incapables d’initier un processus de cicatrisation suite à une lésion, nos résultats démontrent un effet positif de l’atRA sur la migration des cellules épithéliales amniotiques (amniocytes primaires), conduisant ainsi à une potentialisation de la cicatrisation de plus de 80% in vitro. Ce travail, complété par une analyse transcriptomique réalisée sur des membranes fœtales et des amniocytes primaires traités ou non à l’atRA, a permis d’identifier de nombreux gènes régulés par l’atRA au sein de l’amnios et des amniocytes. Parmi ces gènes, je me suis intéressée à un membre de la famille des lysyl oxydases, LOXL4, qui joue un rôle clé dans la dynamique de la matrice extracellulaire en régulant la réticulation du collagène. Une étude de régulation transcriptionnelle associée à de la promotologie ont tout d’abord permis de montrer que l’atRA induisait l’expression du gène LOXL4 de manière directe. Puis, l’inhibition de la protéine LOXL4 lors de tests de blessure (par le β-aminopropionitrile et par un siARN spécifique) nous a permis de démontrer que l’effet pro-cicatrisant de l’atRA était médié, au moins en partie, par la rétino-induction deLOXL4. Ces nouveaux éléments apportés par ce travail dans la compréhension des mécanismes moléculaires utilisés par l’atRA afin de promouvoir la cicatrisation permettent d’envisager son utilisation future dans la prise en charge clinique des ruptures prématurées.

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.

A hiperceratose epidermolítica é uma forma de ictiose geralmente resistente a tratamentos tópicos. Relata-se um caso de paciente feminina , em acompanhamento na dermatologia desde 1978, com diagnóstico de hiperceratose epidermolítica. Foi tratada inicialmente com queratolíticos, vitamina A oral, ácido tartárico e emolientes tópicos, porém sem melhora no quadro clínico, já que não haviam disponíveis outros tratamentos na época. Em 1986, com o advento dos retinóides orais, foi introduzido o etretinato, e em 1998, foi substituído pelo acitretin, apresentando excelente resposta terapêutica. No momento a paciente está em uso de acitretin 25 mg/dia, completando 23 anos de uso de retinóides orais, com mínimos efeitos adversos e melhora significativa na qualidade de vida Epidermolytic hyperkeratosis is a form of ichthyosis normally resistant to topical treatments. Female patient monitored since 1978 diagnosed with epidermolytic hyperkeratosis. Clinical examination showed generalized hyperkeratosis and scaling. Given that no other treatments were available at the time, the patient was initially treated with keratolytic, systemic vitamin A and moisturizers, with no improvement. In 1986, with the development of oral retinoids, etretinate was introduced. In 1998 this was replaced by acitretin. The patient is receiving 25 mg/day after 23 years of using oral retinoids. Significant improvement of the condition and patient's quality of life has been noted