HDAC2 Inhibits Hippocampal Neurogenesis and Impairs the Cognitive Function in Prenatally Stressed Adult Offspring / HDAC2 Inhibe la Neurogénesis del Hipocampo y Afecta la Función Cognitiva en la Descendencia Adulta Estresada Prenatalmente

SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.

El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.

VIH/sida y epigenética / HIV/AIDS and epigenetic

Resumen Desde 1981, el virus de la inmunodeficiencia humana ha afectado a más de 75 millones de personas en el mundo. La prevención, el diagnóstico temprano y, ante todo el empleo de la terapia antirretroviral, ha disminuido su morbimortalidad. Sin embargo, su cura y el desarrollo de una vacuna efectiva aún son objetivos no alcanzables a corto plazo. Una de las barreras para obtener su control es la persistencia crónica de los virus o sus subproductos en los denominados reservorios celulares, lo que induce un proceso inflamatorio crónico complejo que se manifiesta clínicamente como enfermedad cardiovascular, diversos tipos de cáncer, envejecimiento precoz, entre otras patologías. Los procesos intrínsecos que llevan a estos trastornos han estado siendo investigados a profundidad en los últimos años y la epigenética, definida como el estudio de las modificaciones que afectan de manera directa la expresión de los genes, pero sin cambios en la secuencia del ácido desoxirribonuncleico, puede ayudar a desentrañar estos retos. En esta revisión se analizan los mecanismos epigenéticos, como la metilación del ácido desoxirribonuncleico, las modificaciones en histonas y el ácido ribonucleico no codificante, como posibles blancos en el diagnóstico y tratamiento de la inflamación crónica y sus consecuencias clínicas asociadas al virus de inmunodeficiencia humana/sida.

Abstract Since 1981, over 75 million people have been infected with human immunodeficiency virus. The survival rate of patients with this infection has dramatically increased with the use of antiretroviral therapy, and this therapy significantly reduced the incidence of AIDS defining events. Despite recent progress, neither a cure nor a preventive vaccine against human immunodeficiency virus infection is likely to become available soon. Epigenetics is defined as the study of chemical modifications of intrinsic and extrinsic factors of the genetic code regulating gene expression. Three types of epigenetic markers have been found: DNA methylation, post-translational histone modifications, and non-coding RNA (ncRNA). In this review, we analyzed recent research about the relation between epigenetic mechanisms, the persistence of HIV in host cells, the chronic inflammatory response evoked, the cardiovascular diseases associated and premature aging in this population.

La solidez de la investigación homeopática fundamental / The strength of fundamental homeopathic research

La investigación fundamental en homeopatía ha avanzado considerablemente en los últimos 20 años: desde estudios exploratorios con animales y plantas hasta la caracterización de los efectos sistémicos de los medicamentos homeopáticos y estudios in vitro con sistemas celulares aislados para evaluar los cambios en los mecanismos de adaptación celular y señalización intracelular frente a tratamientos homeopáticos variables. El número de artículos publicados a lo largo del tiempo ha permitido realizar varias revisiones sistemáticas. Recientemente, la demostración de que los medicamentos homeopáticos podrían modificar las funciones celulares a través de mecanismos epigenéticos (metilación y desmetilación de ADN) preparó el camino para un campo de investigación completamente nuevo. En paralelo, el descubrimiento de las nanopartículas y propiedades físicas específicas de las diluciones homeopáticas ha arrojado luz hacia un campo antes poco conocido, dado que se consideraba que las diluciones homeopáticas no consistían más que de agua. Así las cosas, los retos para el futuro conciernen a la demostración, o no, de la interrelación entre ambos fenómenos.

Fundamental research in homeopathy has much advanced in the past 20 years. From exploratory studies with animals and plants to the characterization of the systemic effects of homeopathic medicines and in vitro studies with isolated cell systems to assess changes in the mechanisms of cell adaptation and intracellular signaling facing variable homeopathic treatments. The amount of articles published over time enabled several systematic reviews. Recently, demonstration that homeopathic medicines might modify cell functions through epigenetic mechanisms (DNA methylation and demethylation) paved the road for a fully new field of research. In parallel, the discovery of nanoparticles and specific physical properties of homeopathic dilutions brought light to a previously poorly known field, as it was believed that homeopathic dilutions consist in nothing but water. Thus being, challenges for the future concern the demonstration, or not, of the interrelationship between both phenomena.

Salud mental intergeneracional / Intergenerational mental health

La salud mental en distintas generaciones relacionadas entre sí es tema de creciente interés general y científico. El propósito de esta revisión narrativa, necesariamente limitada, es actualizar el conocimiento científico existente, para lo cual se ha seleccionado un total de 72 estudios cualificados de investigación. Los resultados muestran pruebas adecuadas de que la información genética heredable va acompañada de marcas epigenéticas. La combinación de modificaciones genéticas y epigenéticas es importante para determinar la diversidad fenotípica de los progenitores y sus descendientes, y también puede generar múltiples estados psicopatológicos. La llamada programación fetal es un delicado proceso adaptativo de crecimiento prenatal que puede presentar interferencias mórbidas. Existen hipótesis sobre los mecanismos epigenéticos por medio de los cuales las experiencias pre y posnatales programan la reactividad del niño ante situaciones de estrés y promueven el desarrollo de fenotipos adaptativos. Los patrones y procesos del distanciamiento intergeneracional entre familias son sumamente complejos, por lo que es difícil puntualizar conclusiones válidas sobre la salud mental entre generaciones vinculadas. Puede afirmarse, sin embargo, que trastornos mentales graves afectan con frecuencia a múltiples generaciones. La información y el conocimiento sobre este fenómeno requieren, sin duda, de numerosas investigaciones de alta calidad.

SUMMARY Mental health in different related generations is a matter of increasing general and scientific interest. The purpose of this narrative review, necessarily limited, is to update the corresponding scientific knowledge, by selecting a total of 72 qualified research studies. The results show appropriate evidence that inheritable genetic information is accompanied by epigenetic marks. The combination of genetic and epigenetic modifications is important to determine the phenotypic diversity of the progenitors and their descendants, and it also may generate multiple psychopathological states. The so-called fetal programming is a delicate adaptive process of prenatal growth that may be morbidly interfered with. There are hypotheses about epigenetic mechanisms through which prenatal and postnatal experiences program the child's reactivity to stress and promote the development of adaptative phenotypes. The intergenerational distancing patterns and processes among families are very complex, so it is difficult to draw valid conclusions about mental health among linked generations. It can be stated, however, that severe mental disorders often affect multiple generations. Information and knowledge about this phenomenon undoubtedly requires abundant high quality research.

El rol epigenético de la radiación ultravioleta y estrés oxidativo en la formación de cataratas / The Epigenetic Role of Ultraviolet Radiation and Oxidative Stress in Cataract Formation

El ojo humano es altamente expuesto a luz de todo tipo de ondas electromagnéticas, la tensión metabólica en la eliminación del daño celular, así como su acumulación, constituyen el mayor estrés oxidativo debido a radiación ultravioleta. El objetivo del la revisión fue documentar la nueva evidencia científica en epigenética con respecto a la radiación ultravioleta y estrés oxidativo en la formación de cataratas. Se realiza una revisión de la literatura comprendida del 1ro de mayo del 2021 al 1ro de mayo 2022 con meta buscadores en inglés y español. El daño bioquímico acumulable a nivel de las histonas es considerado el primer insulto ambiental en la formación de cataratas. El potencial inmunomodulador de las células del epitelio del lente humano es un blanco terapéutico prometedor, debido a ser la principal línea celular afectada en radiación por rayos ultravioleta. El avance tecnológico, bioquímico y fisiológico permitirá promover una solución diferente, por otro concepto distinto de cirugía, para la cura de la entidad más prevalente en el mundo por ceguera reversible: catarata(AU)

The human eye is highly exposed to light of all types of electromagnetic waves, the metabolic stress in the elimination of cellular damage, as well as its accumulation, constitute the major oxidative stress due to ultraviolet radiation. The objective was to document the new scientific evidence in epigenetics regarding ultraviolet radiation and oxidative stress in cataract formation. A review of the literature from May 1, 2021 to May 1, 2022 was performed with meta-search engines in English and Spanish. Cumulative biochemical damage at the histone level is considered the primary environmental insult in cataract formation. The immunomodulatory potential of human lens epithelium cells is a promising therapeutic target, due to being the main cell line affected in ultraviolet radiation. The technological, biochemical and physiological advance will allow promoting a different solution, by a different concept of surgery, for the cure of the most prevalent condition in the world for reversible blindness: cataract(AU)

Perspectivas con dianas para el tratamiento de la artritis reumatoide / Perspectives with targets for the treatment of rheumatoid arthritis

La artritis reumatoide se clasifica como una enfermedad articular autoinmune crónica poliarticular sistémica que afecta principalmente a manos y pies. El objetivo de este trabajo es mostrar información publicada que contribuye a direccionar el manejo de la artritis reumatoide con nuevos fármacos, a partir del conocimiento de aspectos novedosos relacionados con la fisiopatología y los avances recientes sobre un grupo importante de dianas para el tratamiento de esta enfermedad. Las modificaciones epigenéticas pueden regular la expresión génica sin alterar la secuencia del ADN. La regulación de los ARN no codificantes (ncRNA), la metilación del ADN, la metilación del ARN y las modificaciones de las histonas se consideran los principales mecanismos de las regulaciones epigenéticas. Numerosas investigaciones han establecido que varias anomalías en estos mecanismos terminan en el desarrollo de la AR. Este trabajo resume nuevas dianas, que incluyen proteínas, pequeños metabolitos moleculares y reguladores de la epigenética. Son dianas moleculares prometedoras para el descubrimiento de fármacos que alivien la aparición de enfermedades y resuelvan la falta de respuesta y las respuestas parciales, así como los efectos adversos de los FARME actuales. Es innegable que aún se necesitan mayores esfuerzos para definir con mayor precisión las vías de señalización subyacentes afectadas por estas moléculas recién descubiertas y para desarrollar métodos de terapia apropiados(AU)

Rheumatoid arthritis is classified as a systemic polyarticular chronic autoimmune joint disease that mainly affects the hands and feet. The objective of this work is to show published information that contributes to directing the management of RA with new drugs. Epigenetic modifications can regulate gene expression without altering the DNA sequence. Regulation of non-coding RNAs (ncRNAs), DNA methylation, RNA methylation, and histone modifications are considered the main mechanisms of epigenetic regulations. Numerous investigations have established that various abnormalities in these mechanisms lead to the development of RA. This work summarizes new targets, including proteins, small molecular metabolites and regulators of epigenetics. They are promising molecular targets for drug discovery to alleviate disease onset and resolve non-response and partial responses, as well as adverse effects of current DMARDs. It is undeniable that further efforts are still needed to further define the underlying signaling pathways affected by these newly discovered molecules and to develop appropriate therapy methods(AU)

Etiopathogenesis of drug dependence: an explanatory synthesis from an epigenetic perspective / Etiopatogenia de las drogodependencias: una síntesis explicativa desde una perspectiva epigenética / Etiopatogenia das toxicodependências: uma síntese explicativa a partir de uma perspectiva epigenética

The use of substances with addictive potential is a relevant health problem. Scientific evidence suggests that the underlying mechanisms that regulate behavioral processes in addictions involve a complex interplay between genetic and environmental factors. Therefore, this narrative review aims to provide a framework to synthesize the evidence on gene-environment-agent interactions from the perspective of the natural history of the disease and the stages of the addictive process for alcohol, nicotine, cannabis, psychostimulants, and opioids. In this review, we conducted an exhaustive literature search without time limits in PubMed, Ebsco, Lilacs, and SciELO, reviewing the title and abstract we selected original articles in humans or animals that addressed the etiology of addictions according to the methodological approach of gene-environment (G-E) interaction, including articles in Spanish, English, and Portuguese. Genetic studies have revealed the critical role of epigenetic modifiers (histone acetylation) in maintaining brain homeostasis in pathological conditions and focusing on G-E interactions will also allow characterizing subgroups (based on environmental factors) at high risk for addictive behaviors that can be targeted for specific interventions, Thus, treatment strategies should encompass a combination of psychosocial interventions with gene therapy involving pharmacological manipulations of histones that may contribute to design better therapies and perhaps lead to more successful management of drug dependencies.

El consumo de sustancias con potencial adictivo es un problema relevante de salud. La evidencia científica sugiere que los mecanismos subyacentes que regulan los procesos comportamentales en las adicciones involucran un complejo interjuego entre factores genéticos y ambientales. Por lo tanto, esta revisión narrativa tiene como objetivo aportar un marco de referencia que permita sintetizar la evidencia sobre interacciones genes- ambiente-agente desde la perspectiva de la historia natural de la enfermedad y los estadios del proceso adictivo para: alcohol, nicotina, cannabis, psicoestimulantes y opioides. En esta revisión realizamos una búsqueda exhaustiva de la literatura sin límites de tiempo en PubMed, Ebsco, Lilacs y SciELO, revisando el título y el resumen se seleccionaron artículos originales en humanos o animales que abordaran la etiología de las adiciones según el enfoque metodológico de interacción entre genes y ambiente (G-A), incluyendo artículos en español, inglés y portugués. Los estudios genéticos han revelado el papel crítico de los modificadores epigenéticos (acetilación de las histonas) en mantener la homeóstasis cerebral en condiciones patológicas y enfocarse en las interacciones G-A también permitirá caracterizar subgrupos (basados en los factoresambientales) de alto riesgo para conductas adictivas que pueden ser objeto de intervenciones específicas, por lo que, las estrategias de tratamiento deben englobar una combinación de intervenciones psicosociales con terapia génica que involucren las manipulaciones farmacológicas de las histonas que pueden contribuir a diseñar mejores terapias y tal vez conducir a un manejo más exitoso de las drogodependencias.

O consumo de substâncias com potencial viciante é um relevante problema de saúde. Evidências científicas sugerem que os mecanismos subjacentes que regulam os processos comportamentais em vícios envolvem uma interação complexa entre fatores genéticos e ambientais. Portanto, esta revisão narrativa visa fornecer um quadro de referência que permita sintetizar as evidências sobre interações gene-ambiente-agente sob a perspectiva da história natural da doença e as etapas do processo de dependência para: álcool, nicotina, cannabis, psicoestimulantes e opióides. Nesta revisão, realizamos uma busca exaustiva da literatura sem limites de tempo no PubMed, Ebsco , Lilacs e SciELO, revisando o título e o resumo, foram selecionados artigos originais em humanos ou animais que abordassem a etiologia dos acréscimos de acordo com a abordagem metodológica de interação entre genes e ambiente (GA), incluindo artigos em espanhol, inglês e português. Estudos genéticos revelaram o papel crítico dos modificadores epigenéticos (acetilação de histonas) na manutenção da homeostase cerebral em condições patológicas, e o direcionamento das interações GA também permitirá caracterizar subgrupos (com base em fatores ambientais) de alto risco para comportamentos aditivos que podem ser alvo de ataques específicos. intervenções, portanto, as estratégias de tratamento devem abranger uma combinação de intervenções psicossociais com terapia gênica envolvendo manipulações farmacológicas de histonas que podem contribuir para projetar melhores terapias e talvez levar a um manejo mais bem-sucedido das dependências de drogas.

Obesidade genética não sindrômica: histórico, fisiopatologia e principais genes / Non-syndromic genetic obesity: history, pathophysiology and key genes

A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.

Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.

Caracterización molecular de pacientes con cáncer colorrectal / Molecular characterization of colorectal cancer patients

Introducción. El cáncer colorrectal tiene una alta incidencia en la población mundial. Diversas vías moleculares están involucradas en su desarrollo, entre ellas, la inestabilidad cromosómica, la inestabilidad microsatelital y la epigenética. Objetivo. Hacer la caracterización molecular de 44 individuos con cáncer colorrectal esporádico. Materiales y métodos. El análisis de mutaciones en los genes APC, KRAS, TP53 y BRAF se hizo mediante secuenciación de Sanger; la inestabilidad microsatelital se determinó mediante electroforesis capilar utilizando cinco marcadores de repetición corta en tándem (Short Tandem Repeat) y el estado de metilación del promotor del gen MLH1 se hizo con la técnica MS-PCR (Methylation-Specific PCR). Resultados. La frecuencia de mutación de los genes APC, KRAS y TP53 fue del 18,1, 25 y 4,5 %, respectivamente; las mutaciones detectadas se localizaron con mayor frecuencia en el colon derecho. La frecuencia de inestabilidad microsatelital fue del 27,2 % y el 73,1 % en los tumores con metilación en el gen MHL1, y el 91,6 % de los tumores con inestabilidad microsatelital presentaba metilación en el gen MLH1. En el grupo de tumores con estabilidad microsatelital, las mutaciones en los genes APC, KRAS y TP53 fueron más frecuentes que en el grupo de tumores con inestabilidad microsatelital. La metilación del gen MLH1 fue la alteración más predominante. Conclusiones. En los pacientes con cáncer colorrectal evaluados se demostró la presencia de alteraciones moleculares en las diferentes vías genéticas, las cuales son comunes en su carcinogénesis. Los pacientes presentaron un perfil de mutaciones diferente al de otras poblaciones. Los hallazgos obtenidos en este estudio confirman la heterogeneidad molecular descrita en el desarrollo del cáncer colorrectal.

Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.

Asma tem cura? / Is asthma curable?

A asma é o produto de processos coordenados, interligados e complexos que têm origem nos genes/epigenética, microbioma e ambiente/estilo de vida. Os medicamentos atualmente disponíveis não são capazes de interferir com a inserção da asma no organismo. A abordagem terapêutica atual envolve fármacos que visam controlar os sintomas e antagonizar parte dos efeitos de algumas das citocinas envolvidas. Dessa forma, o tratamento atual visa o controle da asma e não a sua cura. Mecanismos epigenéticos traduzem os estímulos microbiômicos e ambientais em comportamento celular alterado. Por essa razão, a identificação de marcadores epigenéticos certamente apontará novos alvos terapêuticos e, idealmente, estratégias para reverter o comportamento celular alterado no trato respiratório. Aí, sim, poderíamos dizer que a asma tem cura.

Asthma is the product of coordinated, interconnected and complex processes that originate in genes/epigenetics, microbiome, and environment/lifestyle. Currently available drugs are not able to interfere with the insertion of asthma into the body. The current therapeutic approach involves drugs that aim to control symptoms and antagonize part of the effects of some of the cytokines involved. Thus, the current treatment is aimed at controlling asthma and not curing it. Epigenetic mechanisms translate the microbiological and environmental stimuli into altered cellular behavior. For this reason, the identification of epigenetic markers will certainly point out to new therapeutic targets and, ideally, strategies to reverse the altered cellular behavior in the respiratory tract. Then, yes, we could say that asthma is curable.

The possibility of early diagnosis of colorectal cancer through expression of Lncrna UCA1, Lncrna LINC00970, and Wnt genes; an in-vitro study

Colorectal cancer is the 4thcause of cancer death; with considering the growth process of this cancer and the necessity of early diagnosis, the purpose of the research is to state the LncRNA 00970, LncRNA UCAI,and the Wntgene before and after the treatment by 5-Azacytidine epigenetic medicine, to reach the biomarker in the very first steps of colorectal cancer. In this experiment, the human colon cancer cell line (HT29) treated with different concentrations of 5-aza-2'-deoxycytidine (5-aza-dC) was utilized to induce DNA demethylation; Quantitative PCR (qPCR) was used to measure LncRNA UCA1and LncRNA LINC00970 and Wntexpression. There was a significant relationship between the expression of LncRNA 00970, LncRNA UCAI,and the Wntgene and its effects on colorectal (p < 0.05). The Wntgene was treated by 1 and 10 of 5-Azacytidine epigenetic medicine, which then experienced decreases. In LncRNA UCAI and LncRNA00970 in dose 1 micromolar of 5-Azacytidine had decrement and increment of expressionrespectively that explains their efficiency but in treatment by dose 10 mM of this medicine, no significant LncRNA expression difference was detected, 5-azacitidine has a direct impact on its target genes and LncRNAs.Therefore, it can be used in the early diagnosis of colorectal cancer.

Avaliação da expressão da proteína EZH2 em carcinoma adenoide cístico e adenoma pleomórfico / EZH2 immunoexpression in adenoid cystic carcinoma and pleomorphic adenoma

As neoplasias de glândulas salivares apresentam comportamentos diferenciados, que não seguem os padrões clássicos das neoplasias benignas e malignas. A raridade de algumas destas lesões dificulta ainda mais o entendimento dos mecanismos envolvidos na etiopatogenia. Marcadores moleculares como a proteína EZH2 têm sido utilizados na investigação de alterações epigenéticas em diferentes neoplasias, auxiliando na definição do diagnóstico e prognóstico das lesões. O objetivo do presente trabalho é avaliar a expressão da proteína EZH2 e descrever as características clínicas e microscópicas de amostras de carcinoma adenoide cístico (CAC) e adenoma pleomórfico (AP) com ênfase na importância da definição da malignidade da lesão. A análise dos cortes microscópicos corados em Hematoxilina e Eosina dos casos de Adenoma pleomórfico mostraram células epiteliais e mioepiteliais glandulares dispostas em lençóis e estruturas ductiformes em meio a estroma variável. Os casos de Carcinoma adenoide cístico mostraram três padrões distintos de crescimento incluindo formações tubulares, cribriformes e sólidas. Todos os casos de AP e CAC foram positivos para reação imuno-histoquímica para EZH2. As amostras de CAC apresentaram expressão de EZH2 significativamente maior comparado ao AP. As covariáveis metástase em linfonodos, recorrência, padrão histológico, presença de áreas sólidas e invasão perineural foram descritas em relação à marcação de EZH2 em amostras de CAC. Dessa forma, os resultados do estudo melhoram o entendimento das características clínicas e histológicas do CAC, assim como sobre o comportamento das lesões. Além disso, a análise mostra que o EZH2 é um potencial marcador de malignidade e ressalta a importância da validação de marcadores moleculares de alterações epigenéticas.

Salivary gland neoplasms present different behaviors, which do not follow the classic patterns of benign and malignant neoplasms. The rarity of some of these lesions makes it even more difficult to understand the mechanisms involved in the etiopathogenesis. Molecular markers such as the EZH2 protein have been used to investigate epigenetic changes in different neoplasms, helping to define the diagnosis and prognosis of the lesions. The aim of the study was to evaluate the expression of the EZH2 protein and to describe the clinical and microscopic characteristics of adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) which emphasizes the importance of defining the malignancy of the neoplasm. Histopathological analysis of PA cases showed myoepithelial and glandular epithelial cells arranged as duct-like structures and sheets intermingled in the variable stroma and ACC cases showed the three growth patterns, tubular, cribriform and solid forms. All ACC and PA cases were positive for EZH2, with diffuse nuclear staining in neoplastic cells. The ACC samples showed significantly higher EZH2 expression compared to the PA. The covariables nodal metastasis, recurrence, growth pattern, presence of solid areas and perineural invasion have been described in relation to EZH2 staining in ACC samples. The results of the study improve the understanding of the clinical and histological characteristics of ACC, as well as on the behavior of lesions. In addition, the analysis showed that EZH2 is a potential marker of malignancy and highlights the importance of validating molecular markers of epigenetic alterations.

La obesidad y su relación con los contaminantes ambientales, la alimentación y los mecanismos epigenéticos / Obesity related to environmental pollutants, diet and epigenetic mechanisms

Introduction: Obesity is a chronic disease resulting from environmental, psychological and genetic factors. The objective was to carry out a bibliometry of the scientific literature on this pathology related to environmental pollutants, food and epigenetics, to elucidate lines of research. Materials and method: The documents were managed from the Web of Science database. The search strategy was Obesity AND (pollution OR contamination) in the Titles field, AND (epigenetic * OR obesity OR food OR nutrition OR diet) in Themes. 654 articles were found: 577 original investigations and 77 reviews. The articles were exported in BibTeX format to be analyzed with the Bibliometrix program. Results: The evolution of the production of reports per year has been upward. In 2020, the average number of references of the original articles was 38 and of the review articles, 200. Based on the Lotka index combined with the h index, the most prominent author was Joel Schwartz. The United States concentrated the largest production of scientific articles, which coincides with the location of the institutions with the highest affiliation of the authors. The 5 most frequent keywords were: air pollution, particulate matter, obesity, pollution and epigenetics. Conclusions: A line of research on obesity linked to DNA methylation, oxidative stress and PM2.5 is proposed; which will contribute to reducing this pandemic and, therefore, will impact the morbidity and mortality profiles of non-communicable diseases and COVID-19.

Introducción: La obesidad es una enfermedad crónica resultante de factores ambientales, psicológicos y genéticos. El objetivo fue realizar una bibliometría de la literatura científica sobre esta patología relacionada con contaminantes ambientales, alimentación y epigenética, para dilucidar líneas de investigación. Materiales y método: Los documentos se gestionaron de la base de datos Web of Science. La estrategia de búsqueda fue Obesity AND (pollution OR contamination) en el campo Titles, AND (epigenetic* OR obesity OR alimentation OR nutrition OR diet) en Themes. Se encontraron 654 artículos: 577 investigaciones originales y 77 revisiones. Los artículos se exportaron en formato BibTeX para ser analizados con el programa Bibliometrix. Resultados: La evolución que ha tenido la producción de infrmes por año ha sido ascendente. En 2020, el promedio del número de referencias de los artículos originales fue de 38 y de los artículos de revisión, 200. Con base en el índice de Lotka aunado con el índice h, el autor más destacado fue Schwartz. Estados Unidos concentró la mayor producción de artículos científicos, lo que coincide con la ubicación de las instituciones con más adscripción de los autores. Las cinco palabras clave más frecuentes fueron: contaminación del aire, material particulado, obesidad, contaminación y epigenética. Conclusiones: Se propone una línea de investigación sobre la obesidad vinculada con la metilación del ADN, estrés oxidativo y material particulado fino; lo que contribuirá a reducir esta pandemia y por lo tanto, impactará en los perfiles de morbimortalidad de las enfermedades no transmisibles y de la COVID-19.

Triagem biológica de inibidores de sirtuína 2 (TcSir2rp1) candidatos a antichagásicos / Biological screening of sirtuin 2 inhibitors (TcSir2rp1) antichagasic candidates

A doença de Chagas é causada pelo Trypanosoma cruzi, e atualmente, acomete entre 6 a 7 milhões de pessoas em todo o mundo. A quimioterapia disponível para seu o tratamento se baseia apenas em dois fármacos, nifurtimox e benznidazol, com mais de 50 anos de descoberto. Estes fármacos apresentam eficácia limitada, pois são pouco efetivos na fase crônica e apresentam alta toxicidade, resultando em efeitos adversos graves. Esse panorama mostra a necessidade de novas abordagens terapêuticas contra essa doença. Nesse sentido, a inibição de vias bioquímicas essencias para o parasita se mostram como uma boa sugestão para identificação de compostos promissores candidatos a novos agentes quimioterápicos. A sirtuína 2 (Sir2) são enzimas reguladoras que participam de mecanismos epigenéticos em tripanossomatídeos, e no T. cruzi possuem um papel fundamental em todos os seus estágios evolutivos, devido a este fato, se apresentam como um alvo promissor na busca por novos fármacos contra a doença de Chagas. Neste sentido propomos a busca de inibidores da Sir2 proteína 1 do T. cruzi (TcSir2rp1) que é geneticamente validada como alvo farmacológico, por meio da estratégia de triagem biológica. Realizou-se a expressão da enzima recombinante por biologia molecular em um sistema de transformação utilizando cepa de Escherichia coli Artic Express (DE3). Foi feita a purificação e a confirmação da obtenção da proteína recombinante se deu por gel SDS-PAGE. Após a obtenção da enzima os parâmetros cinéticos foram determinados por experimentos de fluorimetria. A triagem foi realizada para um conjunto de 82 compostos, previamente sintetizados pelo nosso grupo de pesquisa, como inibidores da TcSir2p1 em dose única de 100 µM. Os ensaios foram realizados em triplicata e em experimentos independentes. Dentre os 82 compostos testados, 20 apresentaram inibições maior que 50% contra a enzima TcSir2rp1, na dose de 100 µM. Dentre estes, se destacaram 3 compostos derivados de chalconas, para os quais foi determinada a potência. O composto 1 foi o que mais potente, apresentando valor de IC50 de 11,65 µM, já os compostos 3 e 5 foram menos potentes (IC50= 38,50 µM e 19,85 µM, respectivamente). Diante dos resultados obtidos, pode-se concluir que a estratégia de triagem biológica é promissora na identificação de inibidores da TcSir2p1 candidatos a agentes anti- T. cruzi

Chagas disease is caused by Trypanosoma cruzi, and currently affects 6 to 7 million people worldwide. The chemotherapy available for its treatment is based on only two drugs, nifurtimox and benznidazole, with more than 50 years of discovery. These drugs have limited efficacy, as they are ineffective in the chronic phase and have high toxicity, resulting in serious adverse effects. This panorama shows the need for new therapeutic approaches against this disease. In this sense, the inhibition of essential biochemical pathways for the parasite proves to be a good suggestion for the identification of promising compounds candidates for new chemotherapeutic agents. Sirtuin 2 (Sir2) are regulatory enzymes that participate in epigenetic mechanisms in trypanosomatids, and in T. cruzi they have a fundamental role in all their evolutionary stages, due to this fact, they present themselves as a promising target in the search for new drugs against Chagas disease. In this sense, we propose the search for inhibitors of Sir2 protein 1 of T. cruzi (TcSir2rp1) which is genetically validated as a pharmacological target, through the biological screening strategy. The expression of the recombinant enzyme was performed by molecular biology in a transformation system using strain of Escherichia coli Artic Express (DE3). Purification was performed and confirmation of obtaining the recombinant protein was performed by SDS-PAGE gel. After obtaining the enzyme, the kinetic parameters were determined by fluorimetry experiments. Screening was performed for a set of 82 compounds, previously synthesized by our research group, as TcSir2p1 inhibitors in a single dose of 100 µM. Assays were performed in triplicate and in independent experiments. Among the 82 compounds tested, 20 showed inhibitions greater than 50% against the enzyme TcSir2rp1, at a dose of 100 µM. Among these, 3 compounds derived from chalcones stood out, for which the potency was determined. Compound 1 was the most potent, with an IC50 value of 11.65 µM, while compounds 3 and 5 were less potent (IC50= 38.50 µM and 19.88 µM, respectively). In view of the results obtained, it can be concluded that the biological screening strategy is promising in the identification of TcSir2p1 inhibitors candidates for anti-T. cruzi agents

Planejamento, síntese e avaliação biológica de candidatos a fármacos: busca de inibidores epigenéticos da Sirtuína 2 Sir2 / Design, synthesis and biological evaluation of drug candidates: search for Sirtuin 2 (Sir 2) epigenetic inhibitors

As doenças negligenciadas são causadas por agentes infecciosos e parasitários, como vírus, bactérias, protozoários e helmintos. Essas doenças são prevalentes em populações de baixa renda que vivem em países em desenvolvimento e são responsáveis por incapacitar e levar milhares de pessoas à morte. Este nome se dá pois, apesar de sua grande relevância médica, recebem pouca atenção dos governos e indústrias farmacêuticas. Dentre essas doenças podemos destacar a Doença de Chagas, doença infecciosa causada pelo parasita hemoflagelado Trypanosoma cruzi. Endêmica em 21 países, com 6 a 7 milhões de pessoas infectadas resultando em 7500 mortes por ano. A quimioterapia disponível contra essa parasitose é baseada em apenas dois medicamentos, o benznidazol e o nifurtimox, ativos principalmente na fase aguda da doença e com efeitos adversos graves que comprometem a adesão ao tratamento e, além disso, apesar dos enormes esforços na pesquisa de novos agentes antichagásicos em nível nacional e internacional, na maioria realizada academicamente, ainda não foram encontradas alternativas terapêuticas para a doença, persistindo, assim, a necessidade de descoberta e desenvolvimento de novos fármacos. O início de um planejamento de um novo fármaco se dá pela definição de um alvo bioquímico a ser utilizado na busca de moléculas que possam exercer a função de inibidores ou moduladores, conforme a atividade biológica desejada. Neste sentido, as sirtuínas 2 (Sir2) são enzimas que se mostraram essenciais para o crescimento in vitro do T. cruzi em suas formas amastigota e epimastigota. No caso de tripanossomatídeos, em geral, a superexpressão de Sir2 está relacionada à sobrevivência de formas amastigotas. Assim, essas evidências indicam que a Sir2 de tripanosomatídeos tem grande potencial como alvo biológico na busca e desenvolvimento de novos fármacos antichagásicos. O objetivo principal deste projeto foi identificar moléculas que apresentaram atividade inibitória para a sirtuína 2 de T. cruzi por meio da utilização da estratégia de Planejamento de Fármacos Baseada no Ligante - Ligand Based Drug Design (LBDD) e o desenvolvimento de análogos dos inibidores da Sir2. A modificação molecular está entre algumas das técnicas tradicionais usadas no desenvolvimento racional de um fármaco, e é usada principalmente no desenvolvimento de análogos, e busca melhorar as propriedades farmacocinéticas e/ou farmacodinâmicas de um protótipo, obter propriedades de interação semelhantes ao alvo e, em alguns casos, revelar uma atividade biológica. Com este intuito, análogos do sirtinol e da salermida foram sintetizados e uma nova rota sintética utilizando o microrreator em fluxo contínuo foi desenvolvida e apresentou rendimento superior quando comparado à síntese em bancada. A partir desta metodologia foram obtidos 20 compostos. Os ensaios in vitro contra formas amastigotas do T. cruzi indicaram que 8 compostos inibiram a atividade parasitária em mais de 50%, na dose de 10 µM, sendo que alguns destes apresentaram maior inibição parasitária quando comparados ao benznidazol, o fármaco de referência e único disponível no Brasil. Com estes resultados preliminares, novos ensaios estão sendo realizados para identificar potência e mecanismo de ação destes candidatos a agentes tripanomicidas

Neglected diseases are caused by infectious and parasitic agents such as viruses, bacteria, protozoa and helminths. These diseases are prevalent in low-income populations living in developing countries and are responsible for disabling and killing thousands of people. They get this name because, despite their great medical relevance, they end up receiving little attention from governments and pharmaceutical industries. Among these diseases, we can highlight Chagas disease, an infectious endemic disease caused by the hemoflagellate parasite Trypanosoma cruzi. This disease is endemic in 21 countries, with 6 to 7 million people infected resulting in 7,500 deaths per year. Chemotherapy is based on just two drugs, benznidazole and nifurtimox, which are mainly active in the acute phase of the disease. These drugs have adverse effects that compromise adherence, even more, considering that they are not effective from the point of view of the chronic phase of the disease. Despite the enormous efforts in researching new anti-chagasic agents at the national and international level, and mostly carried out academically, therapeutic alternatives for the disease have not yet been found, thus, the need for the discovery and development of new drugs persists. Sirtuins 2 (Sir2) are enzymes that have been shown to be essential for the in vitro growth of T. cruzi in its amastigote and epimastigote forms. In the case of trypanosomatids in general, Sir2 overexpression is related to the survival of amastigote forms. Sir2 inhibitors, such as sirtinol, have shown efficacy in leishmanicides. Thus, these evidences indicate that Sir2 from trypanosomatids can be considered as a biological target in the search and development of new anti-chagasic drugs. The beginning of a new drug planning study is the definition of a biochemical target to be used in the search for molecules that can play the role of inhibitors or modulators, according to the desired biological activity. The main objective of this project was to identify molecules that presented inhibitory activity to sirtuin 2 of T. cruzi using the Ligand Based Drug Design (LBDD) strategy of planning and the development of analogues of Sir2 inhibitors. Molecular modification is a traditional technique used in the rational development of a drug, as well as the use of natural products, combinatorial chemistry, high-throughput screening (HTS), among others. Mainly used in the development of analogues, molecular modification is applied for different purposes, among them, it seeks to improve the pharmacokinetic and/or pharmacodynamic properties of a prototype, obtain target-like interaction properties and, in some cases, reveal an activity biological. For this purpose, analogues of sirtinol and salermide were synthesized and a new synthetic route using the microreactor in continuous flow was developed and presented superior yield when compared to benchtop synthesis. From this methodology, 20 compounds were obtained. in vitro assays against amastigote forms of T. cruzi indicated that 8 compounds inhibited parasitic activity by more than 50% at a dose of 10 µM, and some of these showed greater parasitic inhibition when compared to benznidazole, the reference drug, and only available in Brazil. With these preliminary results, new assays are being carried out to identify the potency and mechanism of action of these candidate trypanocidal agents

Ciência da disseminação em DOHaD para a promoção da saúde nas futuras gerações / Dissemination Science in DOHaD for health promotion in future generations

Após o reconhecimento de princípios evolutivos e da epigenética associada à plasticidade do desenvolvimento, a ciência de DOHaD (Origens Desenvolvimentistas da Saúde e Doença) floresceu. Segundo DOHaD, a exposição a condições adversas no início da vida, como a subnutrição, leva a respostas adaptativas para aumentar as chances de sobrevivência imediata e posterior, as quais podem aumentar o risco de doenças crônicas não transmissíveis (DCNT) no curso da vida. Outros insultos como obesidade (materna e paterna) na preconcepção e gestação, diabetes gestacional, aleitamento e a alimentação inadequada na infância podem induzir respostas não adaptativas e aumentar o risco de doenças, independentemente do ambiente posterior. A exposição à desreguladores endócrinos, substâncias tóxicas e poluentes também podem ter efeitos de longo prazo. Esses efeitos são mediados por alterações epigenéticas, as quais se tornam mais sensíveis nesse período crítico de desenvolvimento de intensa reorganização. Diante da transição nutricional e coexistência das diferentes formas de desnutrição nos países de baixa e média renda (PBMR); do aumento global das DCNT, cujo impacto social e econômico é maior nesses países; da fraca contribuição de fatores genéticos fixos na etiologia dessas doenças; e da ineficácia das atuais intervenções, a implementação de DOHaD representa uma estratégia potencial para beneficiar as futuras gerações. Considerando que a disseminação de DOHaD não têm acompanhado seu florescimento científico, esse trabalho teve como objetivo o desenvolvimento de um ebook direcionado para nutricionistas e um artigo relativo aos impactos da pandemia de COVID-19 na perspectiva de DOHaD, a fim de aproximar a ciência destes profissionais e fomentar sua implementação. Trata-se de uma revisão narrativa de literatura a partir artigos científicos em inglês e português, publicados nas bases de dados SciELO, PubMed e BVS, sem limite de data. O trabalho evidenciou que o desafio da dupla carga de doenças e das diferentes formas de desnutrição nos PBMR, foi agravado pela pandemia, tornando imperativo medidas de intervenção por seu provável impacto no ciclo intergeracional de DCNT e desenvolvimento dos países. A aproximação dessa ciência do nutricionista, propicia uma formação mais ampla e integrativa, através de capacitação técnica e habilidades interpessoais, capazes de acionar as fragilidades biopsicossociais, e melhor intervir, equacionando resultados de curto e longo prazo, a fim de interromper o ciclo intergeracional de DCNT, assim como otimizar o capital humano, a capacidade de produção e renda da futura geração. Conclui-se que o material desenvolvido é de grande valia, dado que a disseminação desse conhecimento deve se estender aos nutricionistas de todas as áreas e ser multiplicado

After evolutionary and epigenetics principles associated with the plasticity of development were recognized, DOHaD (Developmental Origins of Health and Disease) science flourished. According to DOHaD, the exposure to adverse conditions at the beginning of life, like undernutrition, leads to adaptive responses to increased immediate and later odds of survival, which may increase the risk of noncommunicable diseases (NCD) during life. Other conditions such as obesity (maternal and paternal) in preconception and pregnancy, gestational diabetes, lactation, and inadequate nourishment during infancy can induce non-adaptive responses and increased risk of diseases, regardless of the upcoming environment. The exposure to endocrine disruptors, and toxic and pollutant substances can also have long-term effects. Those effects are mediated by epigenetic changes, which become more sensitive during this critical period of development under intense reorganization. Considering the nutritional transition and coexistence of the different forms of undernutrition in the low- and middle-income countries (LMIC); the global increase of NCDs, with a higher social and economic impact in those countries; the weak contribution of fixed genetic factors in the etiology of those diseases; and the inefficacy of current interventions, the implementation of DOHaD represents a potential strategy to benefit future generations. Considering that the dissemination of DOHaD have not followed its scientific progress, the goal of the present work was to develop an e-book targeting nutritionists and an article about the impacts of the COVID-19 pandemic in the perspective of DOHaD, intended to drive the science closer to those professionals and foster its implementation. It is a narrative review of the literature regarding scientific articles published in English and Portuguese on the data bases SciELO, PubMed and BVS, with no date limit. The work has highlighted that the challenge of the double burden of the diseases and the several forms of undernutrition in the LMIC, was aggravated by the pandemic, making intervention measures imperative due to its likely impact on the intergenerational cycle of NCD and the development of countries. By inching closer to nutritionists this science provides larger and more integrative education through technical training and interpersonal abilities that help activate biopsychosocial fragilities, and better intervention; providing short- and long-term results aiming to interrupt the NCD intergenerational cycle, as well as optimize the human capital, the work and income capacity of the future generation. It is concluded that the material developed is of great value, given that the dissemination of this knowledge should reach all nutritionists from all areas and be multiplied

The heterogeneity of systemic lupus erythematosus: Looking for a molecular answer / La heterogeneidad del lupus eritematoso sistémico: buscando una respuesta molecular

ABSTRACT The heterogeneity of SLE is a major limitation when designing clinical trials and understand ing the mechanisms of the disease. The analyses conducted before the new technologies for the identification of the single cell transcriptome focused on the detection of molecular patterns such as interferon signature in total blood or through the analysis of major sepa rate cell populations, such as CD4+ T cells. The analyses of molecular patterns have mainly focused on the transcriptome and DNA methylation changes. The first studies on single cell transcriptomics have now been published for mononuclear blood cells and tissues or the knowledge derived from them, total kidney, tubules and skin keratinocytes. The latter have defined patterns of nonresponse to treatment. However, much work still needs to be done to be able to use these methods in clinical practice.

RESUMEN La heterogeneidad del lupus es una limitante al momento de diseñar estudios clínicos, así como también para nuestra facultad de comprender los mecanismos de la enfermedad. Los análisis previos a las nuevas tecnologías para la detección del transcriptoma de célula única trabajaron en la identificación de patrones moleculares, como la firma del interferón en sangre total, o a través del análisis de poblaciones celulares principales separadas, como son las células T CD4+. Los análisis de patrones moleculares se han enfocado primordialmente en el transcriptoma y en los cambios de metilación del ADN. Ya se han publicado los primeros estudios de transcriptoma de célula única para células sanguíneas mononucleares y para tejidos, riñón total, túbulos y queratinocitos de piel. Estos últimos han definido patrones de no-respuesta al tratamiento. Aún falta mucho para que los métodos o los conocimientos derivados de los mismos sean de utilidad en la práctica clínica.

Geographical Distribution of Access to Healthcare in Patients Diagnosed with Hypospadias / Distribución geográfica del acceso a la asistencia sanitaria en pacientes con diagnóstico de hipospadias

Objective Hypospadias is a congenital disease of unknown etiology involving multiple epigenetic, genetic, and endocrinological factors. It is a highly incapacitating condition. Its surgical management is one of the most frequent surgical procedures done by pediatric urologists. Furthermore, the geographical distribution and healthcare access is limited in Colombia. The Colombian Ministry of Health has consolidated a nationwide registry called Integrated Social Protection Information System (SISPRO, in the Spanish acronym) to collect comprehensive information on the use and frequency of resources associated with health care in Colombia. The aim of the present study was to analyze the number of cases reported between 2014 and 2018 and the geographical distribution of access to healthcare of patients with hypospadias in Colombia. Methods An observational, retrospective study of hypospadias in Colombia, 2014­ 2018, was performed using data extracted from the Individual Health Records System (RIPS) in SISPRO. Satscan, version 9.6 was used to perform a distribution analysis of the georeferenced population using a Poisson model. To visualize the results, the software projected the result onto a Google Earth map. Results Between January 2014 and December 2018, a total of 8,990 cases of hypospadias were evaluated in Colombia. The geographical distribution in the national territory has areas with high evaluation rates. On average, the departments in which the majority of cases were evaluated during the study period were Bogotá, D.C., Antioquia, and Valle del Cauca (2,196, 1,818 and 1,151 cases, respectively). The statistical analysis of the space exploration (►Fig. 1) identified the area with the highest concentration of cases (red) and the areas in which the lowest number of patients was evaluated (blue). The geographical distribution showed increasing trends in areas near the center of the country, especially in the cities of Bogotá, Cali, Ibagué, and Pereira. Conclusion There is a greater concentration of cases evaluated in the center of the country, where the cities with better access to subspecialized medical care are located. This highlights inequalities in health services and the opportunity for surgical care among regions of the country. If we consider that the prevalence rates of hypospadias remain stable, 87% of the patients with hypospadias will not be evaluated by a subspecialist.

Objetivo Hipospadias es una enfermedad congénita de etiología desconocida que involucra múltiples factores epigenéticos, genéticos y endocrinológicos. Es una condición sumamente incapacitante. Su manejo quirúrgico es uno de los procedimientos quirúrgicos más frecuentes realizados por urólogos pediátricos. Además, la distribución geográfica y el acceso a la atención médica son limitados en Colombia. El Ministerio de Salud de Colombia ha consolidado un registro a nivel nacional denominado Sistema Integrado de Información de Protección Social (SISPRO) para recopilar información integral sobre el uso y frecuencia de los recursos asociados a la atención de la salud en Colombia. El objetivo del presente estudio fue analizar el número de casos notificados entre 2014 y 2018 y la distribución geográfica del acceso a la atención médica por los pacientes con hipospadias en Colombia. Métodos Se realizó un estudio observacional y retrospectivo de hipospadias en Colombia, 2014-2018, utilizando datos extraídos del Sistema de Registros Sanitarios Individuales (RIPS) en SISPRO. Se usó Satscan, versión 9.6 para realizar un análisis de distribución de la población georreferenciada usando un modelo de Poisson. Para visualizar los resultados, el software proyectó el resultado en un mapa de Google Earth. Resultados Entre enero de 2014 y diciembre de 2018, se evaluaron un total de 8.990 casos de hipospadias en Colombia. La distribución geográfica en el territorio nacional tiene áreas con mayor concentración de la atención de pacientes con hipospadias, al igual que áreas sin atención de esta condicion. En promedio, los departamentos donde se evaluaron la mayoría de los casos durante el período de estudio fueron Bogotá, D.C., Antioquia, y Valle del Cauca (439.2, 363.6, y 230.2, respectivamente). El análisis estadístico de la exploración espacial ([Figura 1]) identificó el área con la mayor concentración de casos (rojo) y las áreas donde se evaluó el menor número de pacientes (azul). La distribución geográfica mostró tendencias crecientes en áreas cercanas al centro del país, especialmente en las ciudades de Bogotá, Cali, Ibagué y Pereira. Conclusiones Existe una mayor concentración de casos evaluados en el centro del país, donde se encuentran las ciudades con un mejor acceso a atención médica subespecializada. Esto pone de relieve las desigualdades en el acceso a los servicios de salud y la oportunidad de atención quirúrgica entre las regiones del país. Si consideramos que las tasas de prevalencia de hipospadias permanecen estables, aproximadamente el 87% de los pacientes con hipospadias no serán evaluados por un subespecialista.

Speckle type POZ adaptor protein (SPOP) and its role in cancer / La proteína adaptadora Speckle-type POZ (SPOP) y su papel en cáncer

Abstract Proteasomal degradation is an essential regulatory mechanism for cellular homeostasis maintenance. The speckle-type POZ adaptor protein (SPOP) is part of the ubiquitin ligase E3 cullin-3 RING-box1 complex, responsible for the ubiquitination and proteasomal degradation of biomolecules involved in cell cycle control, proliferation, response to DNA damage, epigenetic control, and hormone signaling, among others. Changes in SPOP have been associated with the development of different types of cancer, since it can act as a tumor suppressor mainly in prostate, breast, colorectal, lung cancer and liver cancer, due to point mutations and/or reduced expression, or as an oncogene in kidney cancer by protein overexpression. In endometrial cancer it has a dual role, since it can act as a tumor suppressor or as an oncogene. SPOP is a potential prognostic biomarker and a promising therapeutic target.

Resumen La degradación proteosómica es un mecanismo de regulación esencial para el mantenimiento de la homeostasis celular. La proteína adaptadora Speckle-type POZ (SPOP) hace parte del complejo ubiquitin ligasa E3 cullin-3 RING-box1, encargado de la ubiquitinación y degradación proteosomal de biomoléculas involucradas en el control del ciclo celular, proliferación, respuesta al daño de ADN, control epigenético, señalización hormonal, entre otros. Las alteraciones en SPOP han sido asociadas al desarrollo de diferentes tipos de cáncer, ya que puede actuar como supresor tumoral principalmente en cáncer de próstata, mama, colorrectal y pulmón, debido a mutaciones puntuales y/o expresión reducida o como oncogén en cáncer riñón por sobreexpresión de la proteína. En cáncer endometrial tiene un rol dual, ya que puede actuar como supresor tumoral o como oncogén. SPOP es considerado como un potencial biomarcador pronóstico y un objetivo terapéutico prometedor.

Relevancia del metabolismo del folato en el contexto de enfermedades neurodegenerativas / Relevance of folate metabolism in neurodegenerative disorders

Introducción: Varias enfermedades neurodegenerativas están asociadas a alteraciones en el metabolismo del folato, lo que tiene sustanciales implicaciones fisiopatológicas, clínicas y terapéuticas potenciales. Objetivo: Reflejar la relevancia del metabolismo del folato para enfermedades neurodegenerativas, destacando su significación fisiopatológica y clínica, y sus implicaciones terapéuticas. Material y métodos: Se consultaron las bases de datos especializadas en busca de artículos publicados hasta marzo de 2020. Se emplearon descriptores específicos y operadores booleanos. Se empleó la estrategia de búsqueda avanzada para la selección de los artículos, teniendo en cuenta la calidad metodológica o validez de los estudios. Desarrollo: Fueron identificadas evidencias de asociación entre alteraciones del metabolismo del folato y enfermedades neurodegenerativas. Se han identificado variantes en genes que codifican enzimas involucradas en el metabolismo del folato, y modificaciones en patrones de metilación de ADN, asociadas al riesgo o a la gravedad clínica de las enfermedades de Alzheimer, Parkinson, Huntington, Temblor Esencial y Ataxia Espinocerebelosa tipo 2. Fueron encontradas asociaciones entre enfermedades neurodegenerativas y alteraciones en los niveles de metabolitos del folato, y la frecuencia de micronúcleos. Se han realizado varios estudios observacionales o experimentales que indican que la suplementación con ácido fólico y vitaminas B6 y B12, tiene utilidad terapéutica potencial en el contexto de enfermedades neurodegenerativas. Conclusiones: El metabolismo del folato es de relevancia fisiopatológica, clínica y terapéutica para enfermedades neurodegenerativas. El uso de estrategias dirigidas a restaurar los niveles normales de folatos o de co-factores enzimáticos involucrados en el metabolismo del folato, o a reducir la acumulación de homocisteína, tiene potenciales aplicaciones terapéuticas en el contexto de estas enfermedades(AU)

Introduction: Several neurodegenerative disorders are associated with alterations in folate metabolism, having essential physiopathological, clinical and therapeutic implications. Objective: To assess the relevance of folate metabolism in neurodegenerative disorders, highlighting its physiopathological, clinical and therapeutic significance. Material and Methods: Specialized biomedical databases were searched for studies published up to March 2020. Descriptors and Boolean operators were used. Advanced search strategy was used for the selection of articles, taking into account the methodological quality and validity of the studies. Results: Strong evidence of the association between folate metabolism and neurodegenerative disorders were identified. Enzyme-coding genes involved in folate metabolism and epigenetic DNA modifications associated with increased risk or disease severity in Alzheimer´s, Parkinson´s, and Huntington´s diseases, Essential Tremor, and Spinocerebellar ataxia type 2 were also identified. Associations between neurodegenerative disorders and altered levels of folate metabolites and the frequency of micronuclei were found. A number of observational and experimental studies have demonstrated that the supplementation with folic acid and vitamin B6 and B12 has therapeutic potential in the context of neurodegenerative disorders. Conclusions: Folate metabolism is of physiopathological, clinical and therapeutic relevance for neurodegenerative disorders. The use of strategies to normalize folate levels or enzyme cofactors involved in folate metabolism or to reduce homocysteine levels has potential therapeutic applications for these disorders(AU)