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1.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360774

RESUMO

Trimethyltin (TMT) is an irreversible neurotoxicant. Because prenatal TMT exposure has been reported to induce behavioral changes, this study was conducted to observe gender differences and epigenetic changes using a mouse model. In behavioral testing of offspring at 5 weeks of age, the total times spent in the center, corner, or border zones in the male prenatal TMT-exposed mice were less than those of control unexposed mice in the open-field test. Female TMT-exposed mice scored lower on total numbers of arm entries and percentages of alternations than controls in the Y-maze test with lower body weight. We found that only TMT-exposed males had fewer copies of mtDNA in the hippocampus and prefrontal cortex region than controls. Additional epigenetic changes, including increased 5-methyl cytosine/5-hydroxymethyl cytosine levels in the male TMT hippocampus, were observed. After methylation binding domain (MBD) sequencing, multiple signaling pathways related to metabolism and neurodevelopment, including FoxO signaling, were identified by pathway analysis for differentially methylated regions (DMRs). Increased FOXO3 and decreased ASCL1 expression were also observed in male TMT hippocampi. This study suggests that sex differences and epigenetics should be more carefully considered in prenatal toxicology studies.


Assuntos
Metilação de DNA/efeitos dos fármacos , Hipocampo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Compostos de Trimetilestanho/toxicidade , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Caracteres Sexuais
2.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360879

RESUMO

Globally, breast cancer has remained the most commonly diagnosed cancer and the leading cause of cancer death among women. Breast cancer is a highly heterogeneous and phenotypically diverse group of diseases, which require different selection of treatments. Breast cancer stem cells (BCSCs), a small subset of cancer cells with stem cell-like properties, play essential roles in breast cancer progression, recurrence, metastasis, chemoresistance and treatments. Epigenetics is defined as inheritable changes in gene expression without alteration in DNA sequence. Epigenetic regulation includes DNA methylation and demethylation, as well as histone modifications. Aberrant epigenetic regulation results in carcinogenesis. In this review, the mechanism of epigenetic regulation involved in carcinogenesis, therapeutic resistance and metastasis of BCSCs will be discussed, and finally, the therapies targeting these biomarkers will be presented.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinogênese/genética , Epigênese Genética , Terapia de Alvo Molecular/métodos , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Código das Histonas/efeitos dos fármacos , Código das Histonas/genética , Humanos
3.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445674

RESUMO

Background: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers' blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. Methods: Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population (n = 244), in relation to the child's dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age. HM450 BeadChip arrays were used to assess DNA methylation, with data compared to aflatoxin albumin adduct levels using two approaches; a continuous model comparing aflatoxin adducts measured in samples collected at 18 months to DNA methylation at 24 months, and a categorical time-dose model that took into account aflatoxin adduct levels at 6, 12 and 18 months, for comparison to DNA methylation at 24 months. Results: Geometric mean (95% confidence intervals) for aflatoxin albumin levels were 3.78 (3.29, 4.34) at 6 months, 25.1 (21.67, 29.13) at 12 months and 49.48 (43.34, 56.49) at 18 months of age. A number of differentially methylated CpG positions and regions were associated with aflatoxin exposure, some of which affected gene expression. Pathway analysis highlighted effects on genes involved with with inflammatory, signalling and growth pathways. Conclusions: This study provides further evidence that exposure to aflatoxin in early childhood may impact on DNA methylation.


Assuntos
Aflatoxina B1/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Experiências Adversas da Infância , Aflatoxinas/efeitos adversos , Aflatoxinas/análise , Aflatoxinas/sangue , Albuminas/análise , Pré-Escolar , DNA/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Gâmbia/epidemiologia , Humanos , Lactente , Leucócitos/metabolismo , Masculino
4.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445681

RESUMO

Parthenogenetic embryos have been widely studied as an effective tool related to paternal and maternal imprinting genes and reproductive problems for a long time. In this study, we established a parthenogenetic epiblast-like stem cell line through culturing parthenogenetic diploid blastocysts in a chemically defined medium containing activin A and bFGF named paAFSCs. The paAFSCs expressed pluripotent marker genes and germ-layer-related genes, as well as being alkaline-phosphatase-positive, which is similar to epiblast stem cells (EpiSCs). We previously showed that advanced embryonic stem cells (ASCs) represent hypermethylated naive pluripotent embryonic stem cells (ESCs). Here, we converted paAFSCs to ASCs by replacing bFGF with bone morphogenetic protein 4 (BMP4), CHIR99021, and leukemia inhibitory factor (LIF) in a culture medium, and we obtained parthenogenetic advanced stem cells (paASCs). The paASCs showed similar morphology with ESCs and also displayed a stronger developmental potential than paAFSCs in vivo by producing chimaeras. Our study demonstrates that maternal genes could support parthenogenetic EpiSCs derived from blastocysts and also have the potential to convert primed state paAFSCs to naive state paASCs.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Partenogênese/fisiologia , Ativinas/metabolismo , Animais , Blastocisto/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Técnicas de Cultura Embrionária/métodos , Feminino , Fatores de Crescimento de Fibroblastos/farmacologia , Camadas Germinativas/metabolismo , Camadas Germinativas/fisiologia , Fator Inibidor de Leucemia/farmacologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos ICR , Células-Tronco Embrionárias Murinas/citologia , Partenogênese/genética , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/patologia
5.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444938

RESUMO

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4+ T cells. The biological activities of CD4+ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4+ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4+ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4+ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.


Assuntos
Arginina/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Adulto , Ilhas de CpG , Suplementos Nutricionais , Epigênese Genética , Sangue Fetal/metabolismo , Expressão Gênica , Humanos , Imunidade/genética , Recém-Nascido , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Regiões Promotoras Genéticas
6.
Cytogenet Genome Res ; 161(5): 227-235, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34311462

RESUMO

Inactivation of tumor suppressor genes, such as RAP1GAP, by hypermethylation of their regulatory region can give rise to thyroid tumors. The aim of this study was to investigate the expression of the RAP1GAP gene and the DNA methylation patterns of its CpG74a, CpG74b, and CpG24 in an Iranian population with differentiated thyroid cancer (DTC). In this study, 160 individuals who underwent thyroidectomy in the Tehran Erfan Hospital between 2018 and 2020 were selected. DNA methylation patterns of selected CpG islands (CpG74a, CpG74b, and CpG24) were determined using methylation-specific PCR. The mRNA expression and protein level of -RAP1GAP were also evaluated. SW1736 and B-CPAP cells were treated with 5-aza-2'-deoxycytidine (5-Aza) to demethylate these regions. The hypermethylation rates of CpG74a and CpG24 in DTC samples were significantly higher than in the control. The mRNA expression and protein level of -RAP1GAP were significantly decreased in the DTC group. In the DTC group, hypermethylation in CpG74a was correlated with decreasing RAP1GAP expression (R2: 0.34; p = 0.043). CpG74a with a specificity of 86.4% has significant prediction power to distinguish between DTC and normal thyroid tissues. Additionally, hypermethylation of CpG74a was significantly associated with higher tumor stages (stage III-IV: 77%; stage I-II: 23%; p = 0.012). Increasing expression of RAP1GAP after demethylation with 15 µM of 5-Aza was observed in both cell lines. These results indicate that DNA hypermethylation in CpG74a can be considered as an epigenetic biomarker in DTC.


Assuntos
Adenocarcinoma Folicular/genética , Carcinoma Papilar/genética , Metilação de DNA , DNA de Neoplasias/genética , Epigênese Genética , Proteínas Ativadoras de GTPase/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/cirurgia , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ilhas de CpG/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Decitabina/farmacologia , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos
7.
Nat Genet ; 53(8): 1233-1242, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34326545

RESUMO

The agouti viable yellow (Avy) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. Avy expressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.


Assuntos
Metilação de DNA , Disruptores Endócrinos/toxicidade , Obesidade/genética , Retroelementos , Animais , Compostos Benzidrílicos/toxicidade , Metilação de DNA/efeitos dos fármacos , Dieta/efeitos adversos , Epigênese Genética , Feminino , Ferredoxina-NADP Redutase/genética , Ácido Fólico/genética , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/genética , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Obesidade/etiologia , Fenóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal
8.
Environ Health ; 20(1): 79, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243768

RESUMO

BACKGROUND: Arsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS. METHODS: DNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs. RESULTS: In a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR < 0.05). Using meta-analyzed results, we identified 11 DMRs and 11 DVRs in PBMC samples, and 16 DMRs and 19 DVRs in PBMC and buccal cell samples. One region annotated to LRRC27 was identified as a DMR and DVR. Arsenic-associated KEGG pathways included lysosome, autophagy, and mTOR signaling, AMPK signaling, and one carbon pool by folate. CONCLUSIONS: Using a two-step process of (1) harmonized data processing and analysis and (2) meta-analysis, we leverage four DNAm datasets from two continents of individuals exposed to high levels of As prenatally and during adulthood to identify DMPs and DVPs associated with arsenic exposure. Our approach suggests that standardizing analytical pipelines can aid in identifying biological meaningful signals.


Assuntos
Arsênio/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Leucócitos/metabolismo , Mucosa Bucal/citologia , Efeitos Tardios da Exposição Pré-Natal/genética , Poluentes Químicos da Água/efeitos adversos , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
9.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298869

RESUMO

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in classical epigenetic processes, (ii) screen original biomedical scientific publications including bibliometric analyses, (iii) identify drugs that interact with epigenetic enzymes, including their additional non-epigenetic targets, and (iv) analyze computational functional genomics of drugs with epigenetic interactions. PubMed database search yielded 3051 hits on epigenetics and drugs, starting in 1992 and peaking in 2016. Annual citations increased to a plateau in 2000 and show a downward trend since 2008. Approved and investigational drugs in the DrugBank database included 122 compounds that interacted with 68 unique epigenetic enzymes. Additional molecular functions modulated by these drugs included other enzyme interactions, whereas modulation of ion channels or G-protein-coupled receptors were underrepresented. Epigenetic interactions included (i) drug-induced modulation of DNA methylation, (ii) drug-induced modulation of histone conformations, and (iii) epigenetic modulation of drug effects by interference with pharmacokinetics or pharmacodynamics. Interactions of epigenetic molecular functions and drugs are mutual. Recent research activities on the discovery and development of novel epigenetic therapeutics have passed successfully, whereas epigenetic effects of non-epigenetic drugs or epigenetically induced changes in the targets of common drugs have not yet received the necessary systematic attention in the context of pharmacological plasticity.


Assuntos
Epigênese Genética/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Metilação de DNA/efeitos dos fármacos , Epigenômica/métodos , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Humanos , Canais Iônicos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo
10.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34204008

RESUMO

Assisted reproductive technologies impact transcriptome and epigenome of embryos and can result in long-term phenotypic consequences. Whole-genome DNA methylation profiles from individual bovine blastocysts in vivo- and in vitro-derived (using three sources of protein: reproductive fluids, blood serum and bovine serum albumin) were generated. The impact of in vitro culture on DNA methylation was analyzed, and sex-specific methylation differences at blastocyst stage were uncovered. In vivo embryos showed the highest levels of methylation (29.5%), close to those produced in vitro with serum, whilst embryos produced in vitro with reproductive fluids or albumin showed less global methylation (25-25.4%). During repetitive element analysis, the serum group was the most affected. DNA methylation differences between in vivo and in vitro groups were more frequent in the first intron than in CpGi in promoters. Moreover, hierarchical cluster analysis showed that sex produced a stronger bias in the results than embryo origin. For each group, distance between male and female embryos varied, with in vivo blastocyst showing a lesser distance. Between the sexually dimorphic methylated tiles, which were biased to X-chromosome, critical factors for reproduction, developmental process, cell proliferation and DNA methylation machinery were included. These results support the idea that blastocysts show sexually-dimorphic DNA methylation patterns, and the known picture about the blastocyst methylome should be reconsidered.


Assuntos
Blastocisto/metabolismo , Reprogramação Celular/genética , Meios de Cultura/farmacologia , Epigênese Genética/efeitos dos fármacos , Caracteres Sexuais , Animais , Blastocisto/efeitos dos fármacos , Bovinos , Cromossomos de Mamíferos/genética , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Feminino , Fertilização In Vitro , Ontologia Genética , Modelos Logísticos , Masculino , Anotação de Sequência Molecular , Análise de Componente Principal
11.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209014

RESUMO

Elevated concentrations of heavy metals such as cadmium (Cd) have a negative impact on staple crop production due to their ability to elicit cytotoxic and genotoxic effects on plants. In order to understand the relationship between Cd stress and plants in an effort to improve Cd tolerance, studies have identified genetic mechanisms which could be important for conferring stress tolerance. In recent years epigenetic studies have garnered much attention and hold great potential in both improving the understanding of Cd stress in plants as well as revealing candidate mechanisms for future work. This review describes some of the main epigenetic mechanisms involved in Cd stress responses. We summarize recent literature and data pertaining to chromatin remodeling, DNA methylation, histone acetylation and miRNAs in order to understand the role these epigenetic traits play in cadmium tolerance. The review aims to provide the framework for future studies where these epigenetic traits may be used in plant breeding and molecular studies in order to improve Cd tolerance.


Assuntos
Cádmio/toxicidade , Produtos Agrícolas/crescimento & desenvolvimento , Resistência a Medicamentos , Epigênese Genética/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/genética , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , RNA de Plantas/efeitos dos fármacos , RNA de Plantas/genética
12.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201550

RESUMO

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.


Assuntos
Encéfalo/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Metotrexato/toxicidade , Bainha de Mielina/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/toxicidade , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Ilhas de CpG , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Bainha de Mielina/patologia , Síndromes Neurotóxicas/patologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/genética , Ratos Sprague-Dawley , Fatores de Transcrição SOXE/genética
13.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202589

RESUMO

BACKGROUND: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. METHODS: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. RESULTS: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. CONCLUSION: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.


Assuntos
Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Purinas/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Proteínas Supressoras de Tumor/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Proteínas Supressoras de Tumor/metabolismo
14.
Biomolecules ; 11(5)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070036

RESUMO

Thalassemia, an inherited quantitative globin disorder, consists of two types, α- and ß-thalassemia. ß-thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the ß-globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases ß-globin expression. Down-regulation of γ-globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. ß-thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the ß-thalassemia patient's response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single ß-thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of ß-thalassemia with α-thalassemia ameliorates the ß-thalassemia clinical presentation. In conclusion, the management of ß-thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future.


Assuntos
Epigênese Genética , Globinas beta/genética , Talassemia beta/genética , Autoantígenos/genética , Molécula 1 de Adesão Celular/genética , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Mutação , RNA não Traduzido/genética , Ribonucleoproteínas/genética , Talassemia beta/tratamento farmacológico
15.
Methods Mol Biol ; 2326: 123-141, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097265

RESUMO

Epigenetics is one of the most rapidly expanding fields in biology, which plays important roles in environmental pollutant-induced neurotoxicity. Analyses of epigenetic modification is of great significance in providing more accurate information for the risk assessment and management of harmful factors. However, few studies have systematically summarized the analysis and detection methods for epigenetic modification. In this chapter, we summarized several popular methods for analyses of epigenetic modifications, including Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq) for genome-wide DNA methylation analyses, Quantitative Methylation Specific PCR (qMSP) for genome-specific DNA methylation analyses, methylated RNA immunoprecipitation sequencing (MeRIP-seq) for genome-wide RNA methylation analyses, MeRIP-qPCR for genome-specific RNA methylation analyses, qRT-PCR for the non-coding RNA, and western blot for the histone modification analyses. It could be helpful to the research about environmental epigenetic toxicology.


Assuntos
Poluentes Ambientais/toxicidade , Epigênese Genética/efeitos dos fármacos , Animais , DNA/genética , Metilação de DNA/efeitos dos fármacos , Epigenômica/métodos , Código das Histonas/efeitos dos fármacos , Humanos , Imunoprecipitação/métodos , Reação em Cadeia da Polimerase/métodos , RNA/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de RNA/métodos
16.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066949

RESUMO

Neuroinflammation is one of the most significant factors involved in the initiation and progression of Parkinson's disease. PD is a neurodegenerative disorder with a motor disability linked with various complex and diversified risk factors. These factors trigger myriads of cellular and molecular processes, such as misfolding defective proteins, oxidative stress, mitochondrial dysfunction, and neurotoxic substances that induce selective neurodegeneration of dopamine neurons. This neuronal damage activates the neuronal immune system, including glial cells and inflammatory cytokines, to trigger neuroinflammation. The transition of acute to chronic neuroinflammation enhances the susceptibility of inflammation-induced dopaminergic neuron damage, forming a vicious cycle and prompting an individual to PD development. Epigenetic mechanisms recently have been at the forefront of the regulation of neuroinflammatory factors in PD, proposing a new dawn for breaking this vicious cycle. This review examined the core epigenetic mechanisms involved in the activation and phenotypic transformation of glial cells mediated neuroinflammation in PD. We found that epigenetic mechanisms do not work independently, despite being coordinated with each other to activate neuroinflammatory pathways. In this regard, we attempted to find the synergic correlation and contribution of these epigenetic modifications with various neuroinflammatory pathways to broaden the canvas of underlying pathological mechanisms involved in PD development. Moreover, this study highlighted the dual characteristics (neuroprotective/neurotoxic) of these epigenetic marks, which may counteract PD pathogenesis and make them potential candidates for devising future PD diagnosis and treatment.


Assuntos
Encéfalo/patologia , Epigênese Genética , Inflamação/genética , Inflamação/patologia , Doença de Parkinson/genética , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Progressão da Doença , Humanos
17.
J Biochem Mol Toxicol ; 35(7): e22798, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33969572

RESUMO

This study aimed to investigate the role and possible mechanism of ß-asarone in regulating neuronal apoptosis and axonal regeneration. A scratch injury was applied to cell cultures of mouse primary cortical neurons to mimic neuronal injury. The neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and western blot analysis of apoptosis-related proteins. The axonal regeneration was assessed by immunofluorescent staining of ß-tubulin III and western blot analysis of axonal markers. In the results, ß-asarone inhibited neuronal apoptosis and promoted axonal regeneration by suppressing tumor necrosis factor-α (TNF-α) expression in scratch-injured mouse neuronal cells. Research investigating the molecular mechanisms by which ß-asarone inhibited TNF-α expression showed that, on the one hand, ß-asarone suppressed the JNK/c-Jun pathway and thus transcriptionally inhibited TNF-α expression; on the other hand, ß-asarone induced expression of UHRF1 that recruited DNMT1 to induce TNF-α promoter methylation and subsequently decreased the messenger RNA expression of TNF-α. In conclusion, ß-asarone suppresses TNF-α expression through DNA methylation and c-Jun-mediated transcription modulation in scratch-injured neuronal cells.


Assuntos
Derivados de Alilbenzenos/farmacologia , Anisóis/farmacologia , Metilação de DNA/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transcrição Genética/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Animais , Células Cultivadas , Camundongos
18.
Mol Cell Biochem ; 476(10): 3647-3654, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34050450

RESUMO

Breast cancer is one of the significant causes of death among women diagnosed with cancer worldwide. Even though several chemotherapy combinations are still the primary treatment of breast cancer, unsuccessful treatments, and poor prognostic outcomes are still being reported. DNA methylation and gene expression changes among two breast cancer cell lines representing luminal A (MCF-7) and triple-negative (MDA-MB-231) cancers were determined after sequential combination treatment of doxorubicin and paclitaxel and analyzed using Ingenuity Pathway Analysis. Promoter methylation changes were seen in different treated MCF-7 cells and accompanied by changes in the gene expression of CCNA1 and PTGS2. In MDA-MB-231 cells, the hypomethylation of ESR1 was not accompanied by an increase in its gene expression in any treated cells. The hypomethylation of GSTP1 and MGMT was accompanied by an increase in gene expression levels in the group treated with doxorubicin only. Also, significant downregulation of several genes like MUC1 and MKI67 in MCF-7 cells treated with doxorubicin showed much lower gene expression (- 37.63, - 10.88 folds) when compared with cells treated with paclitaxel (- 2.47, - 2.05 folds) or the combination treatment (- 18.99, - 2.81 folds), respectively. On the other hand, a synergistic effect on MMP9 gene expression was significantly seen in MDA-MB-231 cells treated with the combination (- 9.99 folds) in comparison with the cells treated with doxorubicin (- 3.62 folds) or paclitaxel (1.75 folds) alone. Chemotherapy combinations do not always augment the molecular changes seen in each drug alone, and these changes could be utilized as treatment response markers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Doxorrubicina/farmacologia , Humanos , Células MCF-7 , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
19.
Leukemia ; 35(7): 1873-1889, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958699

RESUMO

Aberrant DNA methylation plays a pivotal role in tumor development and progression. DNA hypomethylating agents (HMA) constitute a class of drugs which are able to reverse DNA methylation, thereby triggering the re-programming of tumor cells. The first-generation HMA azacitidine and decitabine have now been in standard clinical use for some time, offering a valuable alternative to previous treatments in acute myeloid leukemia and myelodysplastic syndromes, so far particularly in older, medically non-fit patients. However, the longer we use these drugs, the more we are confronted with the (almost inevitable) development of resistance. This review provides insights into the mode of action of HMA, mechanisms of resistance to this treatment, and strategies to overcome HMA resistance including next-generation HMA and HMA-based combination therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Animais , Humanos , Resultado do Tratamento
20.
Cancer Sci ; 112(7): 2705-2713, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34009705

RESUMO

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.


Assuntos
Antígenos de Neoplasias/imunologia , Proteínas de Transporte/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Proteínas de Plasma Seminal/imunologia , Animais , Antígenos de Neoplasias/genética , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Epigênese Genética/efeitos dos fármacos , Epitopos de Linfócito T/imunologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/genética , Neoplasias/terapia , Proteínas de Plasma Seminal/genética , Linfócitos T Auxiliares-Indutores/imunologia , Evasão Tumoral/genética
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