Alterações epigenéticas associadas a agenesia dentária não sindrômica: uma revisão sistemática / Epigenetic alterations associated with non-syndromic tooth agenesis: a systematic review

Objetivo: Avaliar se alterações epigenéticas estão associadas à ocorrência da agenesia dentária não sindrômica. Métodos: Buscas computadorizadas foram conduzidas no PubMed, Web of Science, Ovid, Embase e Scopus. Consultas na literatura cinzenta (Open Grey), no Google Scholar e pesquisas manuais nas listas de referências dos artigos incluídos também foram realizadas. Apenas estudos caso-controle avaliando indivíduos com e sem agenesia dentária não sindrômica eram elegíveis. A seleção dos estudos, a extração de dados e a avaliação do risco de viés (ferramenta da Universidade da Adelaide) foram realizadas por dois autores de forma independente. Devido à diferença metodológica dos artigos incluídos, uma meta-análise não foi possível. Resultados: 206 artigos foram identificados nas bases de dados. Após a remoção de 128 duplicatas e a análise de 78 referências, oito artigos preencheram os critérios de elegibilidade e foram incluídos. Os estudos incluídos foram realizados na China, Turquia, Tunísia, Romênia e República Tcheca. As datas de publicação ocorreram entre 2015 e 2023. Os estudos com as menores amostras avaliaram cinco indivíduos com agenesia e cinco sem agenesia e o estudo com a maior amostra avaliou 625 indivíduos com agenesia e 1144 indivíduos sem agenesia. No total, essa revisão analisou 1325 indivíduos com agenesia e 1867 sem agenesia. Dos 33 polimorfismos de nucleotídeo único avaliados, 19 deles estavam potencialmente associados a uma maior suscetibilidade à agenesia dentária não sindrômica, sendo eles identificados nos genes PAX9, AXIN2, WNT10A, MDM2, MSX1 e BMP2. Foram identificadas 29 novas mutações. No geral, os artigos incluídos apresentaram baixo risco de viés. Conclusão: Existe a associação de algumas alterações epigenéticas com a ocorrência de agenesia dentária não sindrômica.

Aim: To assess whether epigenetic alterations are associated with the occurrence of non-syndromic tooth agenesis. Methods: Computerized searches were conducted in PubMed, Web of Science, Ovid, Embase, and Scopus databases. Grey literature searches (Open Grey), Google Scholar, and manual searches in the reference lists of included articles were also performed. Only case-control studies evaluating individuals with and without non-syndromic tooth agenesis were eligible. Study selection, data extraction, and bias assessment (University of Adelaide tool) were independently conducted by two authors. Due to methodological differences in the included articles, a meta-analysis was not feasible. Results: This study identified 206 articles in the databases. After removing 128 duplicates and reviewing 78 references, eight articles met the eligibility criteria and were included. The included studies were conducted in China, Turkey, Tunisia, Romania, and the Czech Republic. Publication dates ranged from 2015 to 2023. Studies with the smallest sample assessed five individuals with agenesis and five without agenesis, and the study with the largest sample assessed 625 individuals with agenesis and 1,144 without agenesis. In total, this review analyzed 1,325 individuals with agenesis and 1,867 without agenesis. Of the 33 single nucleotide polymorphisms evaluated, 19 were potentially associated with an increased susceptibility to non-syndromic tooth agenesis, and these were identified in the PAX9, AXIN2, WNT10A, MDM2, MSX1, and BMP2 genes. Twenty-nine new mutations were identified. Overall, the included articles demonstrated a low risk of bias. Conclusion: There is an association between certain epigenetic alterations and the occurrence of non-syndromic tooth agenesis.

Neurodegeneration and epigenetics: A review / Neurodegeneracion y epigenética: una revisión

Neuronal function and differentiation are tightly regulated by both genome and epigenome. Based on the environmental information the epigenetic changes occur. Neurodegeneration is the consequence of dysregulation of both the genome and epigenome. In this study, we saw different types of alterations of epigenome present in neuronal cells of different model organisms for neurodegenerative disorders. The epigenetic modifications including chromatin modification, DNA methylation, and changes in regulatory RNAs (miRNA) are having a great impact on neurodegenerative disorders as well as memory. The effects of these re-editing in the neuronal cells cause Alzheimer's disease, Parkinson's disease, Huntington's disease but an unusual form of neuroepigenetics has been seen in Prion Disease. Subsequently, for the development of treatment of these diseases, epigenetic modifications should be kept in mind. Although until now many reports came on drug discovery inhibiting histone deacetylases and DNA methyltransferases to reverse the epigenetic change but they lack targeted delivery and sometimes cause a cytotoxic effect on neuronal cells. In future, advancement in targeted and non-cytotoxic drugs should be the main focus for therapeutic treatment of the neurodegenerative disorders.(AU)

La función y diferenciación neuronales están reguladas en gran medida por el genoma y el epigenoma. Los estímulos ambientales producen cambios epigenéticos. La neurodegeneración es consecuencia de una alteración en el genoma y el epigenoma. Hemos analizado diferentes tipos de alteraciones del epigenoma presentes en células neuronales de diferentes modelos animales de enfermedad neurodegenerativa. Los cambios epigenéticos (modificación de la cromatina, metilación del ADN, cambios en los ARN reguladores [miARN]) tienen un impacto importante en las enfermedades neurodegenerativas y en la memoria. Dichos cambios en células neuronales causan diferentes enfermedades, como las de Alzheimer, Parkinson, y Huntington; sin embargo, las enfermedades priónicas muestran formas epigenéticas inusuales. Por tanto, el desarrollo de tratamientos para estas enfermedades debe considerar los cambios epigenéticos. Se han desarrollado diversos fármacos inhibidores de la histona deacetilasa y la ADN metiltransferasa, que revierten los cambios epigenéticos, pero no utilizan sistemas de liberación inteligente, por lo que a veces pueden producir efectos citotóxicos en las células neuronales. La investigación sobre tratamientos para las enfermedades neurodegenerativas debe centrarse en el desarrollo de fármacos no citotóxicos con sistemas de liberación inteligente.(AU)

Neurodegeneration and epigenetics: A review.

Neuronal function and differentiation are tightly regulated by both genome and epigenome. Based on the environmental information the epigenetic changes occur. Neurodegeneration is the consequence of dysregulation of both the genome and epigenome. In this study, we saw different types of alterations of epigenome present in neuronal cells of different model organisms for neurodegenerative disorders. The epigenetic modifications including chromatin modification, DNA methylation, and changes in regulatory RNAs (miRNA) are having a great impact on neurodegenerative disorders as well as memory. The effects of these re-editing in the neuronal cells cause Alzheimer's disease, Parkinson's disease, Huntington's disease but an unusual form of neuroepigenetics has been seen in Prion Disease. Subsequently, for the development of treatment of these diseases, epigenetic modifications should be kept in mind. Although until now many reports came on drug discovery inhibiting histone deacetylases and DNA methyltransferases to reverse the epigenetic change but they lack targeted delivery and sometimes cause a cytotoxic effect on neuronal cells. In future, advancement in targeted and non-cytotoxic drugs should be the main focus for therapeutic treatment of the neurodegenerative disorders.

Evaluación y caracterización de la sirtuina 2.3 de Giardia duodenalis (CdSir2.3)

La giardiasis es la enfermedad gastrointestinal de mayor incidencia mundial, causada por el protozoario Giardia duodenalis, para la cual no se cuenta con una vacuna o tratamiento eficiente. En aras de buscar nuevos blancos farmacológicos contra este parásito, se han estudiado las enzimas del metabolismo energético, como las sirtuinas, deacetilasas dependientes del dinucleótido de adenina y nicotinamida (NAD). Previamente se identificó a GdSir2.1 y GdSir2.2 como deacetilasas dependientes de NAD, con localizaciones subcelulares diferentes. En este trabajo se estudió otro candidato a sirtuina (GdSir2.3) mediante herramientas bioinformáticas para la identificación de características típicas de la familia sirtuina en la secuencia del candidato, y experimentales como la obtención de la proteína recombinante 6xHis-GdSir2.3 que demostró actividad deacetilasa dependiente de NAD y que sirvió como antígeno en la producción de los IgY - α -6xHis-GdSir2.3 para la localización subcelular de la proteína endógena en G. duodenalis. Lo anterior concuerda con otros estudios donde se señala a GdSir2.3 como un importante regulador de la enquistación, debido a su aumento de expresión durante esta etapa del ciclo de vida, constituyéndola como un blanco farmacológico promisorio para el control de esta parasitemia.

Giardiasis is the gastrointestinal disease with the highest incidence worldwide, caused by the protozoan Giardia duodenalis, for which there is no vaccine or efficient treatment. In order to find new pharmacological targets against this parasite, energy metabolism enzymes such as sirtuins, deacetylases dependent on the nicotinamide adenine dinucleotide (NAD), have been studied. GdSir2.1 and GdSir2.2 were previously identified as NAD-dependent deacetylases, with different subcellular locations. In this work, another candidate for sirtuin (GdSir2.3) was studied using bioinformatic tools for the identification of typical characteristics of the sirtuin family in the sequence of the candidate; and experimental ones such as obtaining the recombinant protein 6xHis-GdSir2.3 that demonstrated NAD-dependent deacetylase activity; and that it served as an antigen in the production of IgY - α - 6xHis-GdSir2.3 for the subcellular localization of the endogenous protein in G. duodenalis. The foregoing is consistent with other studies where GdSir2.3 is indicated as an important regulator of encyst due to its increased expression during this stage of the life cycle, constituting it as a promising drug target for the control of this parasitaemia.

A giardíase é a doença gastrointestinal de maior incidência no mundo, causada pelo protozoário Giardia duodenalis, para a qual não existe vacina ou tratamento eficaz. Com o objetivo de encontrar novos alvos farmacológicos contra esse parasita, têm sido estudadas enzimas do metabolismo energético, como as sirtuínas, desacetilases dependentes do dinucleotídeo adenina nicotinamida (NAD). GdSir2.1 e GdSir2.2 foram previamente identificados como desacetilases dependentes de NAD, com diferentes localizações subcelulares. Neste trabalho, outro candidato a sirtuin (GdSir2.3) foi estudado usando ferramentas de bioinformática para a identificação de características típicas da família sirtuin na sequência do candidato; e experimentais, como a obtenção da proteína recombinante 6xHis-GdSir2.3 que demonstrou atividade desacetilase dependente de NAD; e que serviu como antígeno na produção de IgY - α - 6xHis-GdSir2.3 para a localização subcelular da proteína endógena em G. duodenalis. O exposto é consistente com outros estudos em que o GdSir2.3 é apontado como um importante regulador de encisto devido à sua expressão aumentada durante esta fase do ciclo de vida, constituindo-se como um alvo promissor para o controle dessa parasitemia.

Epigenetic changes in headache.

INTRODUCTION: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS: We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS: A total of 15 English-language publications related to the above terms were obtained. CONCLUSION: There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.

Modificaciones epigenéticas en las cefaleas / Epigenetic changes in headache

Introducción: En las cefaleas parece existir una influencia multifactorial, tanto de mecanismos genéticos como ambientales, siendo interesante el estudio de la posible participación de mecanismos epigenéticos en su desarrollo, cronificación y potencial papel como diana terapéutica.MétodosHemos llevado a cabo una revisión bibliográfica, principalmente a través de la base de datos Medline/PubMed, de la implicación de los distintos mecanismos epigenéticos en las cefaleas. Para ello hemos utilizado los términos de búsqueda en inglés: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA y miRNA.ResultadosSe obtuvieron un total de 15 publicaciones en idioma inglés relacionadas con los términos anteriores.ConclusionesExisten indicios de la relación entre la epigenética y las cefaleas, siendo imprescindible, debido al reducido número de estudios, continuar con la investigación de las modificaciones epigenéticas en las cefaleas. Esto podría ayudar a comprender la fisiopatología de las cefaleas e incluso identificar biomarcadores y nuevas dianas terapéuticas más eficaces. (AU)

Introduction: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target.MethodsWe performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA.ResultsA total of 15 English-language publications related to the above terms were obtained.ConclusionThere is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets. (AU)

Neurodegeneration and epigenetics: A review.

Neuronal function and differentiation are tightly regulated by both genome and epigenome. Based on the environmental information the epigenetic changes occur. Neurodegeneration is the consequence of dysregulation of both the genome and epigenome. In this study, we saw different types of alterations of epigenome present in neuronal cells of different model organisms for neurodegenerative disorders. The epigenetic modifications including chromatin modification, DNA methylation, and changes in regulatory RNAs (miRNA) are having a great impact on neurodegenerative disorders as well as memory. The effects of these re-editing in the neuronal cells cause Alzheimer's disease, Parkinson's disease, Huntington's disease but an unusual form of neuroepigenetics has been seen in Prion Disease. Subsequently, for the development of treatment of these diseases, epigenetic modifications should be kept in mind. Although until now many reports came on drug discovery inhibiting histone deacetylases and DNA methyltransferases to reverse the epigenetic change but they lack targeted delivery and sometimes cause a cytotoxic effect on neuronal cells. In future, advancement in targeted and non-cytotoxic drugs should be the main focus for therapeutic treatment of the neurodegenerative disorders.

Trampas extracelulares de neutrófilos en sepsis / Neutrophil extracellular traps in sepsis / Armadilhas extracelulares de neutrófilos na sepse

Resumen: Introducción: Los neutrófilos son uno de los componentes celulares más importantes de la inmunidad innata, debido a que estas células se reclutan rápidamente a los sitios de infección y pueden eliminar patógenos por múltiples métodos. En diferentes entidades, de entre las que se destaca la sepsis, los neutrófilos mejoran sus propiedades antimicrobianas mediante la liberación de trampas extracelulares de neutrófilos (TEN), constituidas por cromatina, histonas y proteínas granulares, proceso que es conocido por NETosis. Objetivo: El objetivo de esta revisión es examinar los conceptos actuales, relacionados con los mecanismos subyacentes de la formación de TEN y su impacto en sepsis. Conclusión: La desregulación de la NETosis causada por sepsis puede tener efectos deletéreos en sepsis, destacando inflamación, trombosis y disfunción multiorgánica.

Abstract: Introduction: Neutrophils are one of the most important cellular components of innate immunity because these cells are rapidly recruited to sites of infection and can eliminate pathogens by multiple methods. In different entities from which sepsis disables neutrophils improve their antimicrobial properties by releasing neutrophils extracellular traps (NET), constituted by chromatin, histones and granular proteins, a process that is known by NETosis. Objective: The objective of this paper is to review current concepts related to the underlying mechanisms of the formation of NETs, as well as the beneficial and harmful effects of them. Conclusions: The dysregulation of NETosis caused by sepsis can have detrimental effects that cause inflammation, thrombosis and multi-organ failure.

Resumo: Introdução: Os neutrófilos são um dos componentes celulares mais importantes da imunidade inata, porque essas células se recrutam rapidamente para locais de infecção e podem matar patógenos por vários métodos. Em diferentes entidades das quais se destaca a sepse, os neutrófilos melhoram suas propriedades antimicrobianas liberando as armadilhas extracelulares de neutrófilos (del inglés: neutrophil extracelular traps, NET), compostas por cromatina, histonas e proteínas granulares, um processo conhecido como NETosis. Objetivo: O objetivo desta revisão é revisar os conceitos atuais relacionados aos mecanismos subjacentes à formação das NET e seu impacto na sepse. Conclusão: A desregulação da NETosis causada pela sepse pode ter efeitos deletérios na sepse, destacando inflamação, trombose e disfunção de múltiplos órgãos.

El ácido valproico como agente sensibilizador al tratamiento anticáncer.

Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

El ácido valproico como agente sensibilizador al tratamiento anticáncer / Valproic acid as a sensitizing agent in anticancer treatment

Resumen El ácido valproico es un fármaco antiepiléptico con más de 50 años de uso clínico. En la década pasada se descubrieron sus efectos anticancerígenos. El análisis de grupos de pacientes que utilizaron este fármaco durante años ha mostrado que disminuye la frecuencia de cáncer de cabeza y cuello. Estudios recientes evidencian el efecto anticáncer al combinar el ácido valproico con la quimioterapia, terapia biológica e inhibidores de sistemas antioxidantes, con resultados excepcionales. En esta revisión se analiza el metabolismo del ácido valproico y su aplicación contra el cáncer.

Abstract Valproic acid is an antiepileptic drug with more than 50 years of clinical use. In the past decade, its anticancer effects were discovered. Analyses in groups of patients who used this drug for years have shown that it decreases the frequency of head and neck cancer. Recent studies show the anticancer effect of combining valproic acid with chemotherapy, biological therapy and antioxidant systems inhibitors, with exceptional results. In this review, we analyze the metabolism of valproic acid and its application against cancer.

Wiedemann-Steiner syndrome with a novel pathogenic variant in KMT2A: a case report / Síndrome de Wiedemann-Steiner por una nueva variante patogénica en KMT2A: reporte de un caso

Abstract Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.

Resumen Descripción del caso: Se reporta el caso de una paciente femenina de un año de edad, diagnosticada con Síndrome de Wiedemann-Steiner basado en la identificación de una nueva variante patogénica de novo de tipo frameshift en el gen KMT2A Mediante secuenciación de exoma usando el enfoque de trio, sumado a sus características clínicas. Hallazgos clínicos: las mutaciones en KMT2A causan el Síndrome de Wiedemann-Steiner, un desorden genético muy raro caracterizado por hipertricosis congénita, talla baja, retardo mental variable y fenotipo facial distintivo, los cuales se encuentran en la paciente reportada. Resultado: La Secuenciación de exoma completo encontró una variante de tipo frameshift: c.4177dupA (p. Ile1393Asnfs * 14) en KMT2A, este cambio a nivel génico genera una alteración de la unión específica a motivos CpG no metilados del DNA a la proteína. El genotipo y el fenotipo de la paciente fue comparado con los pacientes reportados previamente en la literatura. Relevancia clínica: En enfermedades con baja frecuencia como la aquí reportada es necesario establecer correlaciones genotipo-fenotipo que permitan establecer planes terapéuticos y de seguimiento. El análisis realizado no evidenció diferencias atribuibles a sexo o edad entre los pacientes diagnosticados con Síndrome de Weidemann-Steiner. La secuenciación de exoma permitió identificar causalidad en este caso, cuya característica principal de hipertricosis se asocia con alta heterogeneidad clínica y genética.

Análise imuno- histoquímica das proteínas BRCA1 e Acetil Histona H3 no carcinoma de células escamosas oral / Immunohistochemical analysis of BRCA1 and Acetyl Histone H3 proteins in oral squamous cell carcinoma

O carcinoma de células escamosas da região de cabeça e pescoço é o 4° tipo de câncer mais comum em homens no mundo. A Carcinogênese oral é caracterizada por uma heterogeneidade clínica, patológica e biológica, gerando instabilidade genômica e ocasionando a progressão e desenvolvimento de uma desordem potencialmente maligna. O mecanismo DDR (DNA damage response) age como um mecanismo de autodefesa responsável pela manutenção da integridade da cromatina. Sua eficácia é dependente de seu acesso ao local do dano pelas proteínas envolvidas no processo, como as histonas (proteínas que compõem os nucleossomos e que auxiliam no desempacotamento da cromatina). O desequilíbrio da acetilação e deacetilação das histonas em regiões promotoras contribui para a desregulação da expressão gênica e tem sido associado à carcinogênese e à progressão do câncer. O mecanismo DDR é composto por diversas vias de sinalização interconectadas, como as vias do BRCA1. A proteína BRCA1 regula a transcrição, o remodelamento da cromatina, a ubiquitinação e o reparo da quebra de fita dupla de DNA, entre outras funções. Sua identificação tem sido relacionada à quimiorresistência e pior prognóstico, principalmente, em carcinomas de mama e ovário. Assim, o objetivo do estudo foi avaliar a imunoexpressão das proteínas BRCA1 e Acetil Histona H3 em espécimes de biópsia incisional de carcinomas de células escamosas oral (CCEO) em língua móvel, e correlacionar sua expressão com dados epidemiológicos e com a gradação histopatológica dos tumores. Biopsias incisionais de 43 CCEO de língua móvel foram submetidas a análise imuno-histoquímica para os anticorpos BRCA1 e AcH3. As amostram foram microscopicamente subdividas em bem diferenciado (BD) e pouco diferenciado (PD) Todos os casos de CCEO apresentaram marcação nuclear positiva para a ACH3 e não houve correlação estatisticamente significativa entre este anticorpo e a gradação histológica (p=0.391). Todos os casos foram também positivos para a proteína BRCA1. O grupo PD apresentou uma expressão aberrante do BRCA1, com a maioria dos casos possuindo menos que 10% da marcação nuclear (p<0.01). Todos os casos do grupo PD apresentaram marcação citoplasmática (p=0.034). O grupo dos BD mostrou uma expressão majoritariamente nuclear com a maioria dos casos expressando mais de 50% das células positivas (p<0.01). Nossos resultados mostraram que as proteínas AcH3 e BRCA1 foram encontradas expressas em todos os casos de CCEO. Em geral, casos de CCEO apresentaram-se hipoacetilados. Houve uma diminuição significante na expressão da proteína BRCA1 no grupo PD em comparação ao BD. Além disso, a imunomarcação do BRCA1 nos casos PD foi exclusivamente citoplasmática. Nossos estudos corroboram com os achados de trabalhos anteriores para imuno-histoquímica de ambas proteínas BRCA1 e AcH3 em CCEO. O status hipoacetilado do CCEO evidencia a importância das mudanças epigenéticas na carcinogênese oral e na progressão tumoral como sendo um campo de investigação promissor. A imunoexpressão da proteína BRCA1 mostrou um declínio significativo nos casos PD com a proteína, em sua maioria, sendo encontrada no citoplasma. Apesar do estudo ter usado espécimes de biópsia incisional, nosso BRCA1 reproduziu o mesmo observado nos CCEO e em outras neoplasias, sugerindo a possibilidade de seu uso como um marcador prognóstico. (AU)

Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck region and is the fourth most prevalent cancer in men worldwide. The oral carcinogenesis is characterized by a clinical, pathological and biological heterogeneity, causing genomic instability with the progression and development of potentially malignant disorders. The DDR (DNA damage response) pathway acts as a mechanism of self-defense responsible for the detection of the chromatin integrity. Its efficacy is dependent on its access to the site of damage by the proteins involved in the process, such as the histones (proteins that constitute the nucleosomes and assist the packing of the chromatin). The instability of histone acetylation or deacetylation in promoter regions contribute for the dysregulation of the gene expression and has been associated to the carcinogenesis and cancer progression. The DDR mechanism is composed of several interconnected signaling pathways, such as BRCA1 pathways. The BRCA1 protein regulates transcription, chromatin remodeling and repair of double strand DNA breaks and other functions. Its identification has been related to chemoresistance and poor prognostic, especially in mama and ovarian carcinoma. The aim of the study was to evaluate the immunoexpression profile of BRCA1 and AcH3 proteins in fragments of incisional biopsy oral squamous cell carcinomas of the mobile tongue and correlate with the epidemiological data and histopathological gradation of the tumors. Incisional biopsy samples of 43 oral squamous cell carcinoma of the mobile tongue were submitted to immunohistochemical for AcH3 and BRCA1 antibodies. Samples were microscopically graded in well differentiated and the poor differentiated. All OSCC cases showed AcH3 positive nuclear expression and there was no correlation between AcH3 and histological grading (p=0.391). All the OSCC cases were positive for BRCA-1 expression. The PD group showed an aberrant expression of the BRCA1 protein, with most of the cases with less than 10% of nuclear staining (p<0.01). Moreover, all PD cases showed cytoplasmatic staining (p=0.034). The WD cases showed nuclear staining with most of the cases showing more than 50% of positive cells (p<0.01). Our results pointed that the AcH3 and BRCA1 protein were found to be expressed in all OSCC. In general, OSCC cases were hypoacetylated. There was a significant decrease in BRCA1 protein expression in the poor differentiated group in comparison to the well differentiated. Also, BRCA1 immunostaining was cytoplasmatic in the poor differentiated cases. Our results corroborate the few previous studies for both AcH3 and BRCA1 protein immunohistochemistry findings in OSCC. The hypoacetylated status of OSCC highlights the importance of epigenetics changes in oral carcinogenesis and tumor progression as a promising field of investigation. The BRCA1 protein imunnoexpression showed a significant decrease in the PD cases and the protein was mostly found into the cytoplasm. Although the present study used biopsy specimens, our BRCA1 results were the same observed not only in OSCC but in other cancers suggesting it as a promising prognostic marker.

Alteraciones epigenéticas en leucemia linfoblástica aguda / Epigenetic alterations in acute lymphoblastic leukemia

Resumen: La leucemia linfoblástica aguda (LLA) es el tipo de cáncer más frecuente en niños. Aunque se sabe que las alteraciones genéticas constituyen la base de la etiología de la LLA, se ha demostrado que no son suficientes para el desarrollo leucémico; son necesarias alteraciones adicionales, como las modificaciones epigenéticas. En la LLA se han identificado alteraciones de este tipo, como la metilación del DNA, la modificación de histonas y la regulación por RNAs no codificantes. La hipermetilación del DNA en regiones promotoras es una de las alteraciones epigenéticas más frecuentes en LLA: y conlleva al silenciamiento de genes que generalmente son supresores de tumor y, en consecuencia, contribuye a la leucemogénesis. También se han detectado alteraciones en proteínas remodeladoras de histonas, como la sobreexpresión de enzimas desacetilasas de histonas, así como alteraciones en enzimas acetil transferasas y metil transferasas. En la LLA también se altera la expresión de miRNAs, lo cual produce desregulación en la expresión de sus genes blanco. Estas modificaciones epigenéticas son eventos clave en la transformación maligna, e involucran la desregulación de oncogenes como BLK, WNT5B y WISP1 y de supresores de tumor como FHIT, CDKN2A, CDKN2B y TP73, lo que afecta diversos procesos celulares fundamentales que conllevan al desarrollo de LLA. Las alteraciones epigenéticas y genéticas contribuyen en conjunto al desarrollo y evolución de la LLA.

Abstract: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL.

Epigenetic modulators of thyroid cancer.

There are some well known factors involved in the etiology of thyroid cancer, including iodine deficiency, radiation exposure at early ages, or some genetic changes. However, epigenetic modulators that may contribute to development of these tumors and be helpful to for both their diagnosis and treatment have recently been discovered. The currently known changes in DNA methylation, histone modifications, and non-coding RNAs in each type of thyroid carcinoma are reviewed here.

Perspectivas moleculares en cardiopatía hipertrófica: abordaje epigenético desde la modificación de la cromatina / Molecular perspectives in hypertrophic cardiomyopathy: epigenetic approach from chromatin remodeling

Resumen Los cambios epigenéticos inducidos por factores ambientales tienen cada día más relevancia en las enfermedades cardiovasculares. Uno de los componentes moleculares más observados en la hipertrofia cardiaca es la reactivación de los genes fetales causados por diversas patologías que incluyen obesidad, hipertensión arterial, estenosis valvular aórtica, causas congénitas, entre otras. A pesar de las múltiples investigaciones cuyo objetivo es obtener información acerca de los componentes moleculares de esta patología, su influencia en las estrategias terapéuticas es relativamente escasa. En la actualidad se busca información acerca de las proteínas que modifican la expresión de los genes fetales que se reactivan en esta condición. La relación entre las histonas y el ADN tiene un control reconocido en la expresión de genes que son condicionados por el ambiente e inducen modificaciones epigenéticas. Las deacetilasas de histonas son un grupo de proteínas que han demostrado tener un papel importante en la diferenciación de la célula cardiaca y además pueden ser claros componentes en el desarrollo de la hipertrofia cardiaca. En este trabajo se revisan los conocimientos actuales sobre la influencia de estas proteínas y los posibles planes terapéuticos en la hipertrofia cardiaca.

Abstract Epigenetic alterations induced by environmental factors are more relevant each day for cardiovascular diseases. One of the most observed molecular components in hypertrophic cardiomyopathy is the reactivation of fetal genes caused by multiple conditions, including obesity, high blood pressure, aortic valve stenosis and congenital causes. Despite several investigations with the objective of obtaining information regarding molecular components of this condition, its influence in therapeutic strategies is relatively scarce. Nowadays information is being searched about proteins that modify the expression of the fetal genes that reactivate with this condition. The relationship between histones and DNA has a recognised control in the expression of genes that are subject to the environment and induce epigenetic alterations. Histone deacetylases are a group of proteins that have revealed to play an important role in differentiation the cardiac cell and could be clear components in the development of hypertrophic cardiomyopathy. In this study current knowledge about the influence of these proteins and possible therapeutic plans for hypertrophic cardiomyopathy are revised.

Induced pluripotent stem cells reprogramming: Epigenetics and applications in the regenerative medicine / Células-tronco de pluripotência induzida: papel da epigenética na reprogramação e sua aplicabilidade clínica

Summary Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed into an embryonic-like pluripotent state by the expression of specific transcription factors. iPSC technology is expected to revolutionize regenerative medicine in the near future. Despite the fact that these cells have the capacity to self-renew, they present low efficiency of reprogramming. Recent studies have demonstrated that the previous somatic epigenetic signature is a limiting factor in iPSC performance. Indeed, the process of effective reprogramming involves a complete remodeling of the existing somatic epigenetic memory, followed by the establishment of a "new epigenetic signature" that complies with the new type of cell to be differentiated. Therefore, further investigations of epigenetic modifications associated with iPSC reprogramming are required in an attempt to improve their self-renew capacity and potency, as well as their application in regenerative medicine, with a new strategy to reduce the damage in degenerative diseases. Our review aimed to summarize the most recent findings on epigenetics and iPSC, focusing on DNA methylation, histone modifications and microRNAs, highlighting their potential in translating cell therapy into clinics.

Resumo As células-tronco de pluripotência induzida (CTPI) ou do inglês induced pluripotent stem cells (iPSCs) são células somáticas reprogramadas para o estado embrionário por meio da expressão de fatores ectópicos de transcrição específicos, tornando-as um alvo promissor para a medicina regenerativa. Apesar das CTPI compartilharem características embrionárias, como pluripotência e capacidade de autorrenovação, elas possuem uma baixa eficiência de reprogramação, sendo a memória epigenética uma das principais barreiras nesse processo. A epigenética é caracterizada por alterações reversíveis e herdáveis no genoma funcional que não alteram a sequência de nucleotídeos do DNA. Dentre as diferentes modificações epigenéticas, destacam-se metilação de DNA, alterações em histonas e microRNA. Atualmente, sabe-se que o processo de reprogramação efetivo das CTPI envolve um completo remodelamento da memória epigenética somática existente, seguido pelo estabelecimento de uma "assinatura epigenética" que esteja de acordo com o novo tipo de célula a ser diferenciada. Modificações epigenéticas personalizadas são capazes de melhorar o rendimento e a efetividade das CTPI geradas, abrindo uma nova perspectiva para a terapia celular. Nesta revisão reunimos as principais informações sobre os fatores epigenéticos que afetam a reprogramação das CTPI, bem como seus benefícios na aplicação da terapia celular.

[Epigenetic alterations in acute lymphoblastic leukemia]. / Alteraciones epigenéticas en leucemia linfoblástica aguda.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. It is well-known that genetic alterations constitute the basis for the etiology of ALL. However, genetic abnormalities are not enough for the complete development of the disease, and additional alterations such as epigenetic modifications are required. Such alterations, like DNA methylation, histone modifications, and noncoding RNA regulation have been identified in ALL. DNA hypermethylation in promoter regions is one of the most frequent epigenetic modifications observed in ALL. This modification frequently leads to gene silencing in tumor suppressor genes, and in consequence, contributes to leukemogenesis. Alterations in histone remodeling proteins have also been detected in ALL, such as the overexpression of histone deacetylases enzymes, and alteration of acetyltransferases and methyltransferases. ALL also shows alteration in the expression of miRNAs, and in consequence, the modification in the expression of their target genes. All of these epigenetic modifications are key events in the malignant transformation since they lead to the deregulation of oncogenes as BLK, WNT5B and WISP1, and tumor suppressors such as FHIT, CDKN2A, CDKN2B, and TP53, which alter fundamental cellular processes and potentially lead to the development of ALL. Both genetic and epigenetic alterations contribute to the development and evolution of ALL.

[Epigenetics in atherosclerosis]. / Epigenética en la arteriosclerosis.

The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis.

CARACTERIZACIÓN DE LA ESTRUCTURA SECUNDARIA DE SUBTIPOS DE LA HISTONA H1 POR DICROÍSMO CIRCULAR / CHARACTERIZATION OF THE SECONDARY STRUCTURE OF HISTONE H1 SUBTYPES BY CIRCULAR DICHROISM (CD)

Introducción: Las histonas H1 modulan la estructura y la función de la cromatina. Las células somáticas de mamífero contienen los subtipos H1º, H1a, H1b, H1c, H1d y H1e; en células germinales de testículo y en ovocito, se encuentran respectivamente H1t y H1oo. Su estructura está conformada por un dominio central globular flanqueado por los dominios N-Terminal (DNT) y C-Terminal (DCT). Objetivo: Caracterizar la estructura secundaria de subtipos de la histona H1 mediante dicroísmo circular (DC). Materiales y Métodos: La histona H1 total se extrajo de núcleos de cerebro de rata por cromatografía de intercambio catiónico; la H1º se purificó por filtración en gel y las H1a, H1b, H1c y H1e por cromatografía líquida de alta resolución de fase reversa (RF-HPLC). Los espectros de DC se realizaron en tampón fosfato 10 mM; tampón fosfato 10 mM, 20% TFE (trifluoroetanol); tampón fosfato 10 mM, 40% TFE; tampón fosfato 10 mM, 60% TFE; tampón fosfato 10 mM, 150 mM NaCl y tampón fosfato 10 mM, 1 M NaCl. El análisis de los espectros se realizó con el programa Standard Analysis. Resultados: El porcentaje de hélice-alfa se calculó por diferentes métodos matemáticos teniendo en cuenta elipticidad molar a 193 nm y a 222 nm; con programa de deconvolución K2D y con relaciones cualitativas R1 y R2. El TFE induce la estructura en hélice-alfa en cada uno de los subtipos, mientras que NaCl no induce ningún cambio importante. Conclusión: Los subtipos con mayor contenido de hélice-alfa son H1a y H1c. Las diferencias observadas en el porcentaje de hélice-alfa entre los diferentes subtipos puede ser importante para su diferenciación funcional.

H1 histones modulate the structure and function of chromatin. Mammalian somatic cells contain H1º, H1a, H1b, H1c, H1d and H1e subtypes; H1t and H1oo are found in testicular germ cells and oocyte, respectively. Its structure consists of a globular core domain flanked by N-terminal (DNT) and C-terminal (DCT) domains. Objective: To characterize the secondary structure of histone H1 subtypes through circular dichroism (CD). Materials and Methods: Total histone H1 was extracted for rat brain nuclei by cation exchange chromatography; histone H1º was purified by gel filtration and the histones H1a, H1b, H1c and H1e were purified by reversed phase high performance liquid chromatography (RP-HPLC). CD spectra were performed in 10 mM phosphate buffer; 10 mM, 20% TFE phosphate buffer (trifluoroethanol); 10 mM, 40% TFE; phosphate buffer 10 mM, 60% TFE; phosphate buffer 10 mM, 150 mM NaCl and phosphate buffer 10 mm, 1 M NaCl. The analysis of the spectra was performed with JASCO Standard Analysis. Results: The percentage of alpha-helix was calculated using different mathematical methods, taking into account the molar ellipticity at 193 nm, and 222 nm, with K2D deconvolution program and the R1 and R2 qualitative relationships. The results indicate that TFE induced the alpha-helix structure in each of the subtypes, whereas NaCl did not induce any significant change. Conclusion: H1a and H1c are subtypes with highest content of alpha-helix. The observed differences in the percentage of alpha-helix between different subtypes may be important for their functional differentiation.

Epigenética y síndrome metabólico / Epigenetics and Metabolic Syndrome

La epigenética puede definirse como los cambios estables y heredables en la expresión génica, que no son producidos por cambios en la secuencia del ADN. Las modificaciones epigenéticas más estudiadas son la metilación del ADN y las modificaciones postraduccionales de histonas. Estas podrían explicar cómo factores ambientales, nutricionales y otros, contribuyen a la modulación de la expresión de genes y al desarrollo de distintas enfermedades. El síndrome metabólico está definido por la presencia de obesidad, fundamentalmente central, hipertensión, diabetes, dislipemia, y un estado protrombótico y proinflamatorio, que son factores de riesgo de enfermedad cardiovascular. La genética de estas enfermedades es compleja, y es sabido que tanto factores genéticos de susceptibilidad o resistencia, como factores ambientales contribuyen al desarrollo de este síndrome. Nuestro grupo ha estudiado la participación de las modificaciones epigenéticas en la fisio­patología del síndrome metabólico. Ellas podrían tener un rol importante no solo en el desarrollo de estas enfermedades en la vida adulta, sino predisponer al individuo desde desarrollo prenatal. En esta revisión describimos las principales modificaciones epigenéticas, y a través de nuestros hallazgos cómo sería su papel en el desarrollo del síndrome metabólico. Conocer cómo participarían las modificaciones epigenéticas en estas enfermedades, no solo permitirá mejorar el tratamiento de las mismas, sino establecer medidas preventivas desde la gestación. Rev Argent Endocrinol Metab 52:35-44, 2015 Los autores declaran no poseer conflictos de interés.

Epigenetics can be defined as stable and heritable changes in gene expression that are not produced by changes in DNA sequence. The most studied epigenetic modifications are DNA methylation and histone post-translational modifications. Epigenetic modifications might explain how environmental, nutritional and others factors contribute to the modulation of gene expression and the development of different diseases. Metabolic syndrome is defined by the presence of mainly central obesity, hypertension, diabetes, dyslipidemia, and a prothrombotic and proinflammatory state, which are risk factors for cardiovascular disease. The genetic factors of these diseases are complex, and it is known that genetic susceptibility or resistance backgrounds as well as environmental factors contribute to the development of this syndrome. We have studied the in­volvement of epigenetic modifications in the pathophysiology of metabolic syndrome. These modifications might play an important role in the development of these diseases in adulthood, and according to our results, they might also predispose an individual from prenatal life. In this review, we describe the main epigenetic modifications, and which could be their role in the development of metabolic syndrome. Understanding how epigenetic modifications act in these diseases could not only help to identify new avenues of treatment but also to establish preventive measures from gestation. Rev Argent Endocrinol Metab 52:35-44, 2015 No financial conflicts of interest exist.