Decrease of 5-hydroxymethylcytosine in primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoproliferative disorder

Abstract Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-Cell lymphoproliferative disorder (PC-SMTLD) has been considered as a controversial dermatological disease that has been included in cutaneous T-cell lymphoma group, presenting most commonly as a solitary nodule and/or plaque with a specific and characteristic head and neck predilection. Due to the considerable overlap between PC-SMTLD and pseudolymphoma (PL), the differential diagnosis is often challenging. Methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, it has rarely been studied in cutaneous lymphomas. Objectives: The authors aimed to explore the role of differential 5-hmC immunostaining as a useful marker to distinguish PC-SMTLD from PL. Methods: Retrospective case series study with immunohistochemical and immunofluorescence analysis of 5-hmC was performed in PL and PC-SMTLD. Results: Significant decrease of 5-hmC nuclear staining was observed in PC-SMTLD when compared with PL (p<0.0001). By semi-quantitative grade integration, there were statistical differences in the final 5-hmC scores in the two study groups. The IF co-staining of 5-hmC with CD4 revealed a decrease of 5-hmC in CD4+ lymphocytes of PC-SMTLD. Study limitations: The small clinical sample size of the study. Conclusions: The immunorreactivity of 5-hmC in CD4+ lymphocytes was highly suggestive of a benign process as PL. Furthermore, the decrease of 5-hmC nuclear staining in PC-SMTLD indicated its lymphoproliferative status and helped to make the differential diagnosis with PL. © 2023 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Analysis of low back pain through the methylation process in specific genes. Systematic review / Análise da dor lombar através do processo de metilação em genes específicos. Revisão sistemática

ABSTRACT BACKGROUND AND OBJECTIVES: Low back pain is one of the most common complaints. Epigenetics represents a mechanism where the environment can modify gene expression without alterations in the primary DNA sequence. This can be seen in the process of DNA methylation, histone modification, and chromatin reorganization. The objective of this study was to conduct a systematic review on DNA methylation processes related to low back pain. CONTENTS: Data were collected up to March 2023. The search was conducted on the following article search platforms: Scielo, Pubmed, Regional Portal of BVS, and LILACS. Pre-defined keywords were used in Portuguese or English: low back pain, DNA methylation, epigenomics, and epigenetics. All chosen words were verified through Health Sciences Descriptors (DeCS), and English words were verified in MesHterms. Bias risk analysis was identified. 61 genes were highlighted in the 8 articles that met the inclusion criteria. Only 2 studies presented genes in common, but one of them was in animal samples. Each analyzed gene has its particularity in performing processes, thus presenting differences in how it could generate low back pain. All studies included in this review were assessed for risk of bias. CONCLUSION: The identified genes contribute significantly to the development of treatments and scientific knowledge. However, as the topic addressed is relatively new, further studies should be developed.

RESUMO JUSTIFICATIVA E OBJETIVOS: Os sintomas da dor lombar são algumas das queixas mais comuns. A epigenética representa um mecanismo pelo qual o meio pode modificar a expressão gênica sem que ocorra alterações da sequência primária de DNA. Isso pode ser visto em processos de metilação de DNA, modificação de histonas e reorganização de cromatina. O objetivo deste estudo foi realizar uma revisão sistemática sobre o processo de metilação de DNA relacionado à dor lombar. CONTEÚDO: A revisão sistemática foi realizada com os dados coletados até março de 2023. A pesquisa foi realizada nas plataformas de busca de artigos: Scielo, Pubmed, Portal Regional da Biblioteca Virtual da Saúde e LILACS. Foram utilizadas palavras-chaves pré-definidas na língua portuguesa ou inglesa: - dor lombar ou low back pain, metilação de DNA ou DNA methylation, epigenômica ou epigenetic; sendo que todas as palavras escolhidas foram verificadas através dos Descritores em Ciências da Saúde (DeCS) e as palavras na língua inglesa foram verificadas no MeSH terms. A análise do risco de viés foi identificada. Nos oito artigos que preencheram os critérios de inclusão foram destacados 61 genes, sendo que apenas dois trabalhos apresentaram genes em comum, porém um deles em amostras animais. Cada gene analisado possui sua particularidade na realização de processos; portanto, apresentando diferenças na forma como poderá gerar a lombalgia. Todos os estudos incluídos nesta revisão tiveram o risco de viés avaliado. CONCLUSÃO: Os genes identificados podem contribuir para a evolução de tratamentos e conhecimento científico. Porém, como o tema abordado é relativamente novo, mais estudos devem ser desenvolvidos.

Polimorfismo (cag) del gen atxn2 como factor de riesgo relacionado con diabetes mellitus tipo 2 / Polymorphism (cag) of the atxn2 gene as a risk factor related to type 2 diabetes mellitus / Polimorfismo (cag) do gene atxn2 como fator de risco relacionado ao diabetes mellitus tipo 2

La diabetes mellitus tipo 2 (DM2) es una de las patologías con más prevalencia a nivel mundial, se estima que alrededor de 425 millones de habitantes viven actualmente con DM2 según la OMS, la importancia de realizar pruebas moleculares que permitan realizar un diagnóstico temprano conlleva el análisis de varios grupos de genes implicados en el fenotipo diabético con una marcada resistencia a la insulina y en la mayoría de los casos obesidad, entre los cuales están el polimorfismo de CAG(n) en el ATXN2 gen encontrado en el cromosoma 12q24. Objetivo. Conocer el estado actual del gen ATXN2 en relación al número variable de repeticiones en tándem (VNTR) del trinucleótido CAG(n) y su posible asociación con el desarrollo de la diabetes mellitus tipo 2. Metodología. Se llevó a cabo una revisión sistemática mediante la búsqueda de información en las bases de datos de PubMed, Google Scholar y Elsevier. Para ello, se combinaron palabras clave relevantes, como "diabetes mellitus tipo 2", "polimorfismo CAG" y "ATXN2 gen", junto con "Epigenética de la DM2". Se seleccionaron artículos originales y estudios experimentales publicados en revistas de alto impacto utilizando Scimago Journal Ranks para garantizar la calidad de la literatura revisada. Conclusión. Se determinó la relación entre el ATXN2 y el VNTR CAG(n) y la actividad transcripcional del gen en la DM2 y otras patologías neurodegenerativas es evidente. Sin embargo, para profundizar en este tema, es necesario ampliar el campo de estudio en Ecuador y en otros países latinoamericanos, a fin de analizar la variabilidad genética y su posible relación con la DM2 en esta población.

Diabetes mellitus type 2 (DM2) is one of the most prevalent pathologies worldwide, it is estimated that about 425 million inhabitants currently live with DM2 according to WHO, the importance of molecular tests that allow early diagnosis involves the analysis of several groups of genes involved in the diabetic phenotype with marked insulin resistance and in most cases obesity, among which are the CAG(n) polymorphism in the ATXN2 gene found on chromosome 12q24. Objective. To know the current status of the ATXN2 gene in relation to the variable number of tandem repeats (VNTR) of the CAG(n) trinucleotide and its possible association with the development of type 2 diabetes mellitus. Methodology. A systematic review was carried out by searching for information in PubMed, Google Scholar and Elsevier databases. For this purpose, relevant keywords, such as "type 2 diabetes mellitus", "CAG polymorphism" and "ATXN2 gene" were combined with "Epigenetics of DM2". Original articles and experimental studies published in high impact journals were selected using Scimago Journal Ranks to ensure the quality of the reviewed literature. Conclusion. The relationship between ATXN2 and VNTR CAG(n) was determined and the transcriptional activity of the gene in DM2 and other neurodegenerative pathologies is evident. However, in order to go deeper into this topic, it is necessary to expand the field of study in Ecuador and in other Latin American countries, in order to analyze the genetic variability and its possible relationship with DM2 in this population.

La diabetes mellitus tipo 2 (DM2) es una de las patologías con más prevalencia a nivel mundial, se estima que alrededor de 425 millones de habitantes viven actualmente con DM2 según la OMS, la importancia de realizar pruebas moleculares que permitan realizar un diagnóstico temprano conlleva el análisis de varios grupos de genes implicados en el fenotipo diabético con una marcada resistencia a la insulina y en la mayoría de los casos obesidad, entre los cuales están el polimorfismo de CAG(n) en el ATXN2 gen encontrado en el cromosoma 12q24. Objetivo. Conocer el estado actual del gen ATXN2 en relación al número variable de repeticiones en tándem (VNTR) del trinucleótido CAG(n) y su posible asociación con el desarrollo de la diabetes mellitus tipo 2. Metodología. Se llevó a cabo una revisión sistemática mediante la búsqueda de información en las bases de datos de PubMed, Google Scholar y Elsevier. Para ello, se combinaron palabras clave relevantes, como "diabetes mellitus tipo 2", "polimorfismo CAG" y "ATXN2 gen", junto con "Epigenética de la DM2". Se seleccionaron artículos originales y estudios experimentales publicados en revistas de alto impacto utilizando Scimago Journal Ranks para garantizar la calidad de la literatura revisada. Conclusión. Se determinó la relación entre el ATXN2 y el VNTR CAG(n) y la actividad transcripcional del gen en la DM2 y otras patologías neurodegenerativas es evidente. Sin embargo, para profundizar en este tema, es necesario ampliar el campo de estudio en Ecuador y en otros países latinoamericanos, a fin de analizar la variabilidad genética y su posible relación con la DM2 en esta población.

Telomere length, oxidative and epigenetic changes in blood DNA of patients with exacerbated psoriasis vulgaris

Abstract Background The pathogenesis of psoriasis vulgaris involves changes in DNA molecules, genomic instability, telomere attrition, and epigenetic alterations among them. These changes are also considered important mechanisms of aging in cells and tissues. Objective This study dealt with oxidation damage, telomere length and methylation status in DNA originating from peripheral blood of 41 psoriatic patients and 30 healthy controls. Methods Oxidative damage of serum DNA/RNA was determined immunochemically. Real-time PCR was used for the analysis of the telomere length. ELISA technique determined levels of 5-methylcytosine in blood cells' DNA. Results Oxidative damage of serum DNA/RNA was higher in patients than in controls (median, 3758 vs. 2286 pg/mL, p < 0.001). A higher length of telomeres per chromosome was found in patients whole-cell DNA than in controls (3.57 vs. 3.04 kilobases, p = 0.011). A negative correlation of the length of telomeres with an age of the control subjects was revealed (Spearman's rho = -0.420, p = 0.028). Insignificantly different levels of 5-methylcytosine in patients and controls were observed (33.20 vs. 23.35%, p = 0.234). No influences of sex, smoking, BMI, PASI score, and metabolic syndrome on the methylation status were found. Study limitations i) A relatively small number of the participants, particularly for reliable subgroup analyses, ii) the Caucasian origin of the participants possibly influencing the results of the parameters determined, and iii) Telomerase activity was not directly measured in serum or blood cells. Conclusion The study demonstrated increased levels of oxidized DNA/RNA molecules in the serum of patients with exacerbated psoriasis vulgaris. The results were minimally influenced by sex, the presence of metabolic syndrome, or cigarette smoking. In the psoriatic blood cells' DNA, the authors observed longer telomeres compared to healthy controls, particularly in females. Insignificantly higher global DNA methylation in psoriasis cases compared to the controls indicated marginal clinical importance of this epigenetic test performed in the blood cells' DNA.

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.

RNA m6A modification affects tumorigenesis and development of hematological malignancies / 中华检验医学杂志

N6-Methyladenosine (m6A) is one of the most prevalent RNA modifications in mammals. The m6A modification is catalyzed by m6A writers or erasers and involved in various RNA metabolic processes with the recognition by m6A readers. Recently, emerging studies have shown m6A modification is pivotal in fundamental bioprocesses including cell homeostasis and oxidative stress, programmed cell death, cell metabolism, and immune regulation, and accounts for tumoral occurrence and development. To date, abnormal m6A levels and dysregulated related enzymes participate in tumorigenesis and chemoresistance among acute leukemias, chronic myeloid leukemia, multiple myeloma, lymphomas, thus influencing patient prognosis. The mechanisms of m6A modification are sophisticated and varied in different types of malignancies or subtypes. Screening appropriate patients to apply m6A-targeted inhibitors is instructive to the precise treatment of hematological malignancies.

Effects of titanium dioxide nanoparticles on circRNA expression profiles in human hepatocellular carcinoma cells HepG2 / 北京大学学报(医学版)

OBJECTIVE@#To investigate the effect of titanium dioxide nanoparticles (TiO2 NPs) on the expression profile of circular ribonucleic acid (circRNA) in human hepatocytes through in vitro cell experiments, and to attempt to understand the potential mechanism of hepatotoxicity through bioinformatics analysis.@*METHODS@#TiO2 NPs were characterized from the aspects of particle size, shape and agglomeration state. The cell counting kit-8 (CCK8) was used to detect the cytotoxicity of TiO2 NPs against human hepatocellular carcinoma cells (HepG2) after exposure to 0, 1.56, 3.13, 6.25, 12.5, 25, 50, 100, and 200 mg/L TiO2 NPs for 24 h or 48 h. The cells were treated at doses of 0 mg/L TiO2 NPs (control group) and 100 mg/L TiO2 NPs (treatment group), and collected after exposure for 48 h, and then RNA from the extracted cell samples was collected and sequenced. The differential circRNAs between the control and the TiO2 NPs treatment groups were screened, and then the enrichment pathway of the differential circRNA target gene was analyzed by multivariate statistics. According to the sequencing results, significantly altered genes and important genes in the significant enrichment pathways were screened, and real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) was performed to verify the results.@*RESULTS@#TiO2 NPs were spherical anatase with a hydrated particle size of (323.50±85.44) nm and a Zeta potential of (-21.00±0.72) mV in a serum-free medium. The results of the CCK8 cytotoxicity assay showed that with the increase of TiO2 NPs concentration, cell viability gradually decreased. A total of 11 478 circRNAs were found by RNA sequencing. Compared with the control groups, TiO2 NPs treatment groups (100 mg/L) had a total of 89 differential circRNAs, of which 59 were up-regulated and 30 were down-regulated. Analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed that the targeted genes of differential circRNAs were mainly enriched in fatty acid degradation, Fanconi anemia pathway, and fatty acid metabolism. The expression levels of circRNA.6730, circRNA.3650 and circRNA.4321 were significantly different between the TiO2 NPs treatment group and the control group, which were consistent with the sequencing results.@*CONCLUSION@#TiO2 NPs can induce changes in circRNA expression profile, and epigenetics may play an important role in the mechanism of hepatotoxicity.

Evaluation of the promoter methylation status of hypoxia factor 3A and interleukin-6 genes and expression levels of mir-130b and mir-146b in childhood obesity

SUMMARY OBJECTIVE: Obesity, which causes many serious diseases, is increasing exponentially in childhood across the world. Epigenetic changes, as well as genetics, play an important role in the process of adipogenesis. Therefore, we aimed to examine the expression levels of obesity-related MicroRNA-130b and MicroRNA-146b and the methylation status of hypoxia factor 3A and interleukin-6 genes associated with obesity in children. METHODS: This study was performed with 98 individuals (49 obese children and 49 controls) whose DNA was isolated from peripheral blood. Gene promoter methylations were analyzed by methylation-specific Polymerase chain reaction. In addition, expression levels of MicroRNAs were determined by quantitative real-time Polymerase chain reaction in 30 children (15 obese children and 15 controls). RESULTS: Methylation status of interleukin-6 gene was 93.9% in obese children (n=46/49) and 100% (n=49/49) in control group (p>0.05). There was no methylation for hypoxia factor 3A gene (p>0.05). As a result of the study, there was no statistically significant difference in terms of methylation status for hypoxia factor 3A and interleukin-6 genes in the obese group compared to the control group. However, we found that expression levels of MicroRNA-130b (p<0.01) and MicroRNA-146b (p<0.001) were higher in the obese group. CONCLUSIONS: Results support that MicroRNA-130b and MicroRNA-146b are potential biomarkers for the prevention and early diagnosis of obesity. This is the first study on childhood obesity in the Middle Black Sea region of Turkey. We believe that the results obtained by expanding the studies in our country and neighboring countries will be more decisive.

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.

A systematic review and meta-analysis of observational studies on the effects of epigenetic factors on serum triglycerides

ABSTRACT Epigenetic modifications might be associated with serum triglycerides (TG) levels. This study aims to systematically review the studies on the relationship between the methylation of specific cytosine-phosphate-guanine (CpG) sites and serum TG levels. This systematic review and meta-analysis study was conducted according to the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. A systematic literature search was conducted in Medline database (PubMed), Scopus, and Cochrane library up to end of 2020. All observational studies (cross-sectional, case-control, and cohort) were included. Studies that assessed the effect of DNA methylation of different CpG sites of ABCG1, CPT1A, and SREBF1 genes on serum TG levels were selected. The National Institutes of Health (NIH) checklist was used to assess the quality of included articles. Among 2790 articles, ten studies were included in the quantitative analysis and fourteen studies were included in the systematic review. DNA methylation of ABCG1 gene had significant positive association with TG levels (β = 0.05, 95% CI = 0.04, 0.05, P heterogeneity < 0.001). There was significant inverse association between DNA methylation of CPT1A gene and serum TG levels (β = −0.03, 95% CI = −0.03, −0.02, P heterogeneity < 0.001). DNA methylation of SREBF1 gene was positively and significantly associated with serum TG levels (β = 0.03; 95% CI = 0.02-0.04, P heterogeneity < 0.001). DNA methylation of ABCG1 and SREBF1 genes has positive association with serum TG level, whereas this association is opposite for CPT1A gene. The role of epigenetic factors should be considered in some populations with high prevalence of hypertriglyceridemia.

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 immunomodulatory effect of lactic acid within the tumor microenvironment / 药学学报

Tumor cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate even under the circumstance of abundant oxygen. This phenomenon of aerobic glycolysis is known as the Warburg effect. Lactic acid, as an important tool for tumor cells to modify the tumor microenvironment, promotes the process of tumor invasion and metastasis, and contributes to tumor development by inducing and recruiting immunosuppression-related cells and molecules. Lactic acid could efflux out of the cancer cells via the monocarboxylate transporters to prevent intracellular acidification. Lactate can inhibit the cytolytic activity of T cells and natural killer (NK) cells, promoting the differentiation of tolerogenic interleukin 10 (IL-10)-producing dendritic cells. Moreover, the lactate-derived lactylation of histone lysine residues can promote macrophage polarization toward the M2-like phenotype, suppressing the immune response within the tumor microenvironment. In this review, we discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion from the aspects of lactic acid metabolism and its effect on immune cells. And we explore the possibility of targeting potential targets in lactate metabolism for tumor treatment. At last, we proposed a tumor immunotherapy strategy by inhibiting the pathway of aerobic glycolysis and proteins associated with the production and transport of lactic acid.

Research progress of omics technology in the field of diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Diabetic retinopathy(DR)is one of the common and severe ocular complications of diabetes mellitus, representing a leading cause of blindness among working-age people. Currently, the pathogenesis of DR is not been explained, and the treatment effect is quite limited in advanced stage. In recent years, it has been revealed in some studies that DR could produce a particularly remarkable performance in genomics, transcriptomics, epigenomics, proteomics and metabolomics. With the rapid development of high-throughput sequencing and detection technology, different omics techniques can explore the occurrence and development mechanism of DR from different omics levels. This paper introduces the research progress of DR in different omics techniques,as well as the new direction of integration analysis in multiomics with DR, and finally discusses the current existing problems and future prospects of omics technology. Therefore, the application of different omics techniques to explore the occurrence and development of DR on different levels contributes a novel idea to unraveling the pathophysiological mechanism of DR and identifying new biomarkers and therapeutic targets.

Neural mechanism of environmental enrichment improving depression / 中华行为医学与脑科学杂志

Depression is a common psychiatric disorder characterized by low mood with complex pathophysiological mechanisms and poor effect of pharmacological treatment.The animals were placed in greater sensory, physical and/or social stimuli than those of the standard feeding environment, so that they can obtain positive plasticity and adaptability.Environmental enrichment(EE) is a common intervention to improve brain function in laboratory.A large number of studies have shown that EE had significant ameliorative effects on various animal models of depression, but the mechanisms have not been yet fully understood with outcome heterogeneity in ethology.There was no universally accepted and unified paradigm and standard for EE due to its multi-dimensionality and complexity.Therefore, it is necessary to improve the structural components and implementation steps of EE by integrating the existing data.Combined with recent studies on animal models of depression, this paper reviewed the anti-depression mechanism of EE from promoting hippocampal neurogenesis, reducing neuroinflammation, regulating neuroendocrine and affecting epigenetic modifications, in order to provide new ideas for mechanisms research and treatment of depression.As the rise of precision medicine and individualized medicine brings human growing interest in exploring the sources and mechanisms of inter-individual differences and intra-group effects of depression, it will be a challenge to translate EE to the human society in a rational way.

Carcinogénesis Oral y Epigenética

RESUMEN: A pesar de que los procesos epigenéticos son estudiados ampliamente de forma general, no se habían relacionado, hasta ahora, a las alteraciones genéticas más tradicionales asociadas en la etiopatogenia del cáncer oral. La visión de carcinogénesis tradicional y la de la epigenética convergen en las mismas vías moleculares involucradas en el desarrollo del cáncer, potenciándose durante el proceso de carcinogénesis oral. A continuación se realizará una revisón de las siguientes vías moleculares VEGF-C /VEGFR; HB-EGF /EGFR; Wnt /B-catenina y las ciclinas, desde un punto de vista genético y epigenético para establecer su conexión durante el proceso de carcinogénesis oral.

ABSTRACT: Although epigenetic processes are widely studied, no one has related them to the classical genetic processes in oral cancer etiopathogenesis. The traditional carcinogenesis and epigenetic views converge in the same molecular pathways involved in cancer development, enhancing this process. This review will approach the VEGF-C/VEGFR, HB-EGF/EGFR, Wnt /B-catenin, and cyclins molecular pathways from the genetic and epigenetic views to establish their connection during the oral cancer process.

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)

Nutrition and Cardiovascular Diseases: Programming and Reprogramming

Abstract The Developmental Origin of Health and Disease (DOHaD) is an area of science dedicated to studying the processes by which insults during critical periods of mammals development leading to physiological changes resultig in diseases throughout life. Studies point to a complex interaction between nutritional status in early life and cardiovascular system homeostasis in which maternal malnutrition during gestation and/or lactation, as well as early weaning, are associated with development of cardiovascular diseases in adulthood. In this context, epigenetic changes, such as DNA methylation, histone acetylation, and change in microRNA expression have been considered molecular bases of cellular plasticity, which can also be gender-dependent. Experimental studies have demonstrated that interventions encompassing the consumption of functional food/bioactive compounds, as well as energetic and nutrients adjustments on the diet, may attenuate or even prevent consequences associated with plasticity of development, improving cardiovascular health. This review aimed to gather and discuss the findings within this context, published over the last ten years.

Screening of DNA methylation sites associated with melanoma and construction of an aberrant methylation profile: a preliminary study / 中华皮肤科杂志

Objective:To screen aberrant DNA methylation sites associated with melanoma using gene chip technology, and to preliminarily construct a melanoma-specific methylation profile.Methods:The Illumina Human Methylation 450K whole-genome methylation chip was used to detect the whole-genome DNA in 6 melanoma tissues and their paralesional skin tissues, and DNA differentially methylated sites were obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) -based pathway analysis were carried out to investigate gene functions.Results:Gene chip testing showed that there were 27 779 differentially methylated sites between melanoma tissues and paralesional tissues, of which 16 673 were hypermethylated sites and 11 106 were hypomethylated sites in melanoma tissues. According to more stringent screening criteria " P < 0.01 and |Δβ| > 0.2", a total of 4 883 differentially methylated sites were screened out after filtering out all single nucleotide polymorphism-related probes, probes located on the XY chromosomes and cross-reactive probes, 1 459 (30%) of which were located in the promoter region including TSS1500, TSS200, 5′UTR and 1st Exon. GO enrichment analysis showed that differentially methylated genes were involved in many biological processes, including cell growth, differentiation, adhesion, movement and migration, signal transduction, transcriptional regulation, etc. KEGG-based pathway analysis showed that differentially methylated genes were mainly involved in signaling pathways, such as focal adhesion pathway, cancer pathways, transforming growth factor-β signaling pathway, phosphatidylinositol signaling pathway, melanogenesis pathway, chemokine signaling pathway, adhesion junction pathway, calcium signaling pathway, cell adhesion molecule pathway, mitogen-activated protein kinase signaling pathway, Wnt signaling pathway, Janus kinase-signal transducer and activator of transcription signaling pathway. Based on the criteira "the top 16 most differentially methylated genes related to hypermethylated sites in the promoter region, the genes with the highest methylation frequency (CpG sites ≥ 7) , the genes with certain functions or involved in a certain signaling pathway", 8 genes (KAAG1, DGKE, SOCS2, TFAP2A, GNMT, GALNT3, ANK2 and HOXA9) were selected as candidate biomarkers for melanoma. Conclusion:There are many hypermethylated genes in melanoma tissues, and 8 differentially methylated genes may serve as biomarkers for melanoma.

Research and application of liquid biopsy based on epigenetic markers in the diagnosis and treatment of solid tumors / 国际肿瘤学杂志

Epigenetic changes are closely related to carcinogenesis, tumor progression and prognosis, which have a considerable potential in assisting the precision and minimally invasive management of cancers. The progress of detection techniques for DNA methylation, hydroxymethylation and histone modification has promoted the research works of liquid biopsy targeting epigenetic markers, and recently, important progress has been made in tumor location, early diagnosis, clinical staging, evaluation of treatment response, monitoring of recurrence and prognostic prediction of solid tumors.