RESUMO
Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of chemotherapy drugs could help better treat patients. Targeted therapies have significantly improved the median overall survival of colorectal cancer patients. One of the standard chemotherapy regimens used for colorectal cancer is capecitabine, which is important in monotherapy and combination therapies. Capecitabine, with other chemotherapeutic agents (irinotecan, oxaliplatin, perifosine, 17-allylamino-17-demethoxygeldanamycin, aspirin, celecoxib, statins, quinacrine, inositol hexaphosphate and inositol, cystine/theanine, curcumin, and isorhamnetin), and biological ones (antibodies) plays an important role in the inhibition of some signaling pathways, increasing survival, reducing tumor growth and side effects of capecitabine. However, some drugs, such as proton pump inhibitors, are negatively related to capecitabine; therefore, the purpose of this work is to review and discuss the performance of capecitabine combination therapies in colorectal cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Quimiocinas/biossíntese , Metilação de DNA/fisiologia , Receptores ErbB/antagonistas & inibidores , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Transdução de SinaisRESUMO
BACKGROUND: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15-17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding. RESULTS: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15-17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15-17 years, but not between birth and age 7 years. CONCLUSIONS: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.
Assuntos
Aleitamento Materno , Metilação de DNA/fisiologia , Ingestão de Alimentos/genética , Fenômenos Fisiológicos da Nutrição do Lactente/genética , Longevidade/genética , Adolescente , Alimentação com Mamadeira , Criança , Pré-Escolar , Epigênese Genética , Epigenômica , Feminino , Sangue Fetal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , MasculinoRESUMO
Acupuncture has been widely used for treating diseases since the ancient days in China, but the mechanism by which acupuncture exerts such powerful roles is unclear. Epigenetics, including DNA methylation, histone modification, and post-transcriptional regulation of miRNAs, is the study of heritable changes in gene expression that do not include DNA sequence alterations. Epigenetics has become a new strategy for the basic and clinical research of acupuncture in the last decade. Some investigators have been trying to illustrate the mechanism of acupuncture from an epigenetics perspective, which has shed new lights on the mechanisms and applications of acupuncture. Moreover, the introduction of epigenetics into the regulatory mechanism in acupuncture treatment has provided more objective and scientific support for acupuncture theories and brought new opportunities for the improvement of acupuncture studies. In this paper, we reviewed the literatures that has demonstrated that acupuncture could directly or indirectly affect epigenetics, in order to highlight the progress of acupuncture studies correlated to epigenetic regulations. We do have to disclose that the current evidence in this review is not enough to cover all the complex interactions between multiple epigenetic modifications and their regulations. However, the up-to-date results can help us to better understand acupuncture's clinical applications and laboratory research.
Assuntos
Terapia por Acupuntura , Epigenômica/métodos , Montagem e Desmontagem da Cromatina/fisiologia , Metilação de DNA/fisiologia , Código das Histonas/fisiologia , Humanos , MicroRNAs/fisiologiaRESUMO
DNA methylation represents an important epigenetic regulation of the genome. Earlier studies have suggested that dietary phenolic compounds including those contained in coffee, tea and soy products may modulate the level of DNA methylation. In this study, we first characterize the effect of caffeic acid phenethyl ester (CAPE) and other dietary phenolic compounds on DNA methylation in vitro. The IC50 values of CAPE, daidzein, isorhamnetin and genistein are 7.6, 6.9, 6.2, and 4.3 µM, respectively, in an in-vitro enzymatic assay system. Computational analysis indicates that CAPE, daidzein, isorhamnetin and genistein can bind inside the DNA substrate-binding site in human DNMT1 with a favorable binding energy. In an animal study, we find that maternal CAPE treatment shifts the coat color distribution of the 21-day-old Avy/a offspring towards the yellow phenotype, indicating that CAPE inhibits the methylation of the agouti gene promoter sequence in vivo. The results from this study may shed light on the potential epigenetic effect in the offspring resulting from maternal intake of certain coffee phenolics during pregnancy.
Assuntos
Ácidos Cafeicos/farmacologia , Café , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Simulação de Acoplamento Molecular/métodos , Álcool Feniletílico/análogos & derivados , Polifenóis/farmacologia , Animais , Ácidos Cafeicos/química , Ácidos Cafeicos/toxicidade , Café/efeitos adversos , Metilação de DNA/fisiologia , Relação Dose-Resposta a Droga , Epigênese Genética/fisiologia , Feminino , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Álcool Feniletílico/toxicidade , Polifenóis/química , Polifenóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Estrutura Secundária de Proteína , SalmãoRESUMO
Neuromodulation techniques have shown promising efficacy on memory function and understanding the epigenetic mechanisms contributing to these processes would shed light on the molecular outcomes essential for cognition. In this review, we highlight some epigenetic mechanisms underlying neuromodulation and regulatory effects of neuronal activity-induced DNA methylation on genes that are highly involved in memory formation. Next, we examine the evidence to support DNA methyltransferase 3a, methyl-CpG binding protein 2, and DNA demethylase as possible memory modulation targets. Finally, we report the recent developments in the field of neuromodulation and explore the potential of these techniques for future neuroepigenetic research.
Assuntos
Metilação de DNA/fisiologia , Terapia por Estimulação Elétrica , Epigênese Genética/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Animais , DNA Metiltransferase 3A , Hipocampo/metabolismo , HumanosRESUMO
OBJECTIVE: In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Maori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed. RESULTS: Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts. CONCLUSION: These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.
Assuntos
Imunidade Adaptativa/genética , Metilação de DNA/fisiologia , Gota/genética , Gota/imunologia , Imunidade Inata/genética , Osteogênese/genética , Transdução de Sinais/genética , Transcrição Gênica , Estudos de Coortes , Feminino , Redes Reguladoras de Genes , Humanos , Leucócitos Mononucleares , MasculinoRESUMO
DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined "epigenetic clock", with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.
Assuntos
Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Terapia de Relaxamento , Idoso , Envelhecimento/genética , Epigênese Genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Projetos Piloto , Resultado do TratamentoRESUMO
Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion.
Assuntos
DNA Glicosilases , Metilação de DNA/fisiologia , DNA de Plantas , Oryza , Proteínas de Plantas , Pólen , Arabidopsis/enzimologia , Arabidopsis/genética , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , DNA de Plantas/genética , DNA de Plantas/metabolismo , Oryza/enzimologia , Oryza/genética , Óvulo Vegetal/enzimologia , Óvulo Vegetal/genética , Desenvolvimento Vegetal/fisiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pólen/enzimologia , Pólen/genéticaRESUMO
Therapeutic hypothermia is commonly used during cardiopulmonary bypass (CPB) to protect the heart against myocardial injury in cardiac surgery. Patients who suffer from chronic hypoxia (CH), such as those with certain heart or lung conditions, are at high risk of severe myocardial injury after cardiac surgery, but the underlying mechanisms are unknown. This study tested whether CH attenuates hypothermic cardioprotection during CPB. Using a rat model of CPB, we found that hypothermic cardioprotection was impaired in CH rats but was preserved in normoxic rats. Cardiac proteomes showed that cold-inducible RNA binding protein (CIRBP) was significantly (P = 0.03) decreased in CH rats during CPB. Methylation analysis of neonatal rat cardiomyocytes under CH and myocardium specimens from patients with CH showed that CH induced hypermethylation of the Cirbp promoter region, resulting in its depression and failure to respond to cold stress. Cirbp-knockout rats showed attenuated hypothermic cardioprotection, whereas Cirbp-transgenic rats showed an enhanced response. Proteomics analysis revealed that the cardiac ubiquinone biosynthesis pathway was down-regulated during CPB in Cirbp-knockout rats, resulting in a significantly (P = 0.01) decreased concentration of ubiquinone (CoQ10). Consequently, cardiac oxidative stress was aggravated and adenosine 5'-triphosphate production was impaired, leading to increased myocardial injury during CPB. CoQ10-supplemented cardioplegic solution improved cardioprotection in rats exposed to CH, but its effect was limited in normoxic rats. Our study suggests that an individualized cardioprotection strategy should be used to fully compensate for the consequences of epigenetic modification of Cirbp in patients with CH who require therapeutic hypothermia.
Assuntos
Hipóxia/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ubiquinona/metabolismo , Animais , Antioxidantes/metabolismo , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Humanos , Hipóxia/tratamento farmacológico , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas de Ligação a RNA/genética , Ratos , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
RNA-based processes play key roles in the regulation of eukaryotic gene expression. This includes both the processing of pre-mRNAs into mature mRNAs ready for translation and RNA-based silencing processes, such as RNA-directed DNA methylation (RdDM). Polyadenylation of pre-mRNAs is one important step in their processing and is carried out by three functionally specialized canonical nuclear poly(A) polymerases in Arabidopsis thaliana. Null mutations in one of these, termed PAPS1, result in a male gametophytic defect. Using a fluorescence-labelling strategy, we have characterized this defect in more detail using RNA and small-RNA sequencing. In addition to global defects in the expression of pollen-differentiation genes, paps1 null-mutant pollen shows a strong overaccumulation of transposable element (TE) transcripts, yet a depletion of 21- and particularly 24-nucleotide-long short interfering RNAs (siRNAs) and microRNAs (miRNAs) targeting the corresponding TEs. Double-mutant analyses support a specific functional interaction between PAPS1 and components of the RdDM pathway, as evident from strong synergistic phenotypes in mutant combinations involving paps1, but not paps2 paps4, mutations. In particular, the double-mutant of paps1 and rna-dependent rna polymerase 6 (rdr6) shows a synergistic developmental phenotype disrupting the formation of the transmitting tract in the female gynoecium. Thus, our findings in A. thaliana uncover a potentially general link between canonical poly(A) polymerases as components of mRNA processing and RdDM, reflecting an analogous interaction in fission yeast.
Assuntos
Polinucleotídeo Adenililtransferase/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Metilação de DNA/genética , Metilação de DNA/fisiologia , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Pólen/metabolismo , Polinucleotídeo Adenililtransferase/genética , RNA de Plantas/genética , RNA de Plantas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismoRESUMO
DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3AD329A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.
Assuntos
Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Crescimento/genética , Animais , Animais Recém-Nascidos , DNA Metiltransferase 3A , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/fisiologia , Transtornos do Crescimento/patologia , Histonas/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação Puntual/fisiologia , Ligação Proteica/genética , Domínios Proteicos/genética , Processamento de Proteína Pós-Traducional/fisiologiaRESUMO
We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation.
Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Espermina/metabolismo , Adenosilmetionina Descarboxilase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA/fisiologia , DNA Metiltransferase 3A , Metilases de Modificação do DNA/metabolismo , Eflornitina/metabolismo , Células Epiteliais/metabolismo , Humanos , Células Jurkat , Glândulas Mamárias Humanas/metabolismo , Ornitina Descarboxilase/metabolismo , Poliaminas/metabolismo , Putrescina/metabolismo , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/metabolismo , Espermidina/metabolismo , DNA Metiltransferase 3BRESUMO
DNA methylation is involved in epigenetic mechanisms associated with gene suppression, and its abnormalities lead to gene instability and disease development. As an essential trace element in humans and animals, selenium (Se) is also associated with abnormal changes in DNA methylation. However, the effect of low Se on DNA methylation in avian tissues has not been reported. In the current study, chickens were fed a low-Se diet (0.033 mg Se/kg) or supplemented with 0.15 mg Se/kg as selenite for up to 55 days. DNA methylation levels were examined by high-performance liquid chromatography (HPLC). DNA methyltransferases (DNMTs) and methyl-DpG-binding domain protein 2 (MBD2) mRNA levels were examined through the applications of RT-PCR. The experiment aims to explore the relationship between low Se and DNA methylation. The results showed that total DNA methylation levels in the muscle tissues, brain, immune tissues, and liver of the low-selenium diet group were decreased compared with the control group. The degree of DNA methylation reduction in different tissues from largest to smallest was liver > cerebellum > thymus > brain > spleen ≥ leg muscles > pectoral muscles > bursa of Fabricius > thalamus > wing muscles. DNMT1, DNMT3A, and DNMT3B mRNA expression levels of the low-selenium diet group were decreased compared with those in the control group. The mRNA expression of the MBD2 gene was increased. The results indicate that low Se can reduce the DNA methylation levels of tissues, especially within the liver. These conclusions provide a basis for exploring the pathogenesis of selenium deficiency from the perspective of DNA methylation and create a new basis for comparative medicine.
Assuntos
DNA (Citosina-5-)-Metiltransferases/metabolismo , Selênio/farmacologia , Animais , Galinhas , Cromatografia Líquida de Alta Pressão , Metilação de DNA/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , RNA Mensageiro/metabolismo , DNA Metiltransferase 3BRESUMO
Perimenopause marks initiation of female reproductive senescence. Age of onset is only 47% heritable suggesting that additional factors other than inheritance regulate this endocrine aging transition. To elucidate these factors, we characterized transcriptional and epigenomic changes across endocrine aging using a rat model that recapitulates characteristics of the human perimenopause. RNA-seq analysis revealed that hypothalamic aging precedes onset of perimenopause. In the hypothalamus, global DNA methylation declined with both age and reproductive senescence. Genome-wide epigentic analysis revealed changes in DNA methylation in genes required for hormone signaling, glutamate signaling, and melatonin and circadian pathways. Specific epignetic changes in these signaling pathways provide insight into the origin of perimenopause-associated neurological symptoms such as insomnia. Treatment with 5-aza-2'-deoxycytidine, a DNA-methyltransferase-1 inhibitor, accelerated transition to reproductive senescence/ whereas supplementation with methionine, a S-adenosylmethionine precursor, delayed onset of perimenopause and endocrine aging. Collectively, these data provide evidence for a critical period of female neuroendocrine aging in brain that precedes ovarian failure and that DNA methylation regulates the transition duration of perimenopause to menopause.
Assuntos
Envelhecimento/genética , Envelhecimento/fisiologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Sistemas Neurossecretores/fisiologia , Perimenopausa/genética , Perimenopausa/fisiologia , Envelhecimento/efeitos dos fármacos , Animais , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , Decitabina/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epigenômica , Feminino , Estudo de Associação Genômica Ampla , Hipotálamo/fisiologia , Menopausa , Metionina/farmacologia , Perimenopausa/efeitos dos fármacos , Ratos Sprague-Dawley , Reprodução , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transcrição GênicaRESUMO
The study aimed to investigate the effects of maternal dietary methyl donors on the performance of sows and their offspring, and the associated hepatic insulin-like growth factor-1 (IGF-1) expression of the offspring. A total of 24 multiparous sows were randomly fed the control (CON) or the CON diet supplemented with methyl donors (MD) at 3 g/kg betaine, 15 mg/kg folic acid, 400 mg/kg choline and 150 µg/kg VB12 , from mating until delivery. After farrowing, sows were fed a common lactation diet through a 28-days lactation period and six litters per treatment were selected to be fed until at approximately 110 kg BW. Maternal MD supplementation resulted in greater birthweight (p < 0.05) and increased the piglet weights (p < 0.01) and litter weights (p < 0.05) at the age of day 28, compared with that in CON group. The offspring pigs in the MD group had greater ADG (p < 0.05) and tended to lower F:G ratio (p = 0.07) compared with that of CON group from day 28 to 180 of age. The offspring pigs from MD group had greater serum IGF-1 concentrations and expressions of hepatic IGF-1 gene and muscular IGF-1 receptor (IGF-1r) protein at birth (p < 0.05), and greater hepatic IGF-1 protein (p = 0.03) and muscular IGF-1r gene expressions (p < 0.05) at slaughter, than that from the CON group. Moreover, the methylation at the promoter of IGF-1 gene in the liver of newborn piglets and finishing pigs was greater in the MD group than that of the CON group (p < 0.05). In conclusion, maternal MD supplementation throughout gestation could enhance the birthweight and postnatal growth rate of offspring, associated with an increased expression of the IGF-1 gene and IGF-1r, as well as the altered DNA methylation of IGF-1 gene promotor.
Assuntos
Metilação de DNA/fisiologia , Proteínas Alimentares/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Suínos/crescimento & desenvolvimento , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Peso ao Nascer , Metilação de DNA/genética , Dieta , Suplementos Nutricionais , Feminino , Expressão Gênica , Fator de Crescimento Insulin-Like I/genética , Lactação , GravidezRESUMO
BACKGROUND/OBJECTIVES: Folate, vitamin B6, vitamin B12, and methionine are involved in DNA synthesis and methylation and thus may modulate pancreatic cancer risk. We investigated these associations in a population-based case-control study conducted in 1994-1998. SUBJECTS/METHODS: Cases (n = 150) were identified from all hospitals in the metropolitan areas of the Twin Cities and the Mayo Clinic, Minnesota. Controls (n = 459) were selected randomly from the general population and were frequency matched to cases by age, sex, and race. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for risk of pancreatic cancer in relation to intake of nutrients considered. RESULTS: Dietary intake of folate was associated with a reduced pancreatic cancer risk [OR (95% CI) for quartile (Q) 4 vs. Q1: 0.31 (0.12-0.78)]. A composite score (range from 2 to 8), reflecting combined dietary intake of folate and vitamin B6, was also inversely associated with pancreatic cancer risk [OR (95% CI) for Q4 vs. Q1: 0.24 (0.08-0.70)]. Null associations were found for intake of vitamin B12 and methionine. CONCLUSIONS: Dietary folate intake was associated with a reduced pancreatic cancer risk, and this association became stronger when dietary intake of folate and vitamin B6 was combined in analysis.
Assuntos
Dieta , Ácido Fólico/administração & dosagem , Metionina/administração & dosagem , Neoplasias Pancreáticas/epidemiologia , Vitamina B 12/administração & dosagem , Vitamina B 6/administração & dosagem , Adulto , Idoso , Estudos de Casos e Controles , Metilação de DNA/fisiologia , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota/epidemiologia , Razão de Chances , Neoplasias Pancreáticas/prevenção & controle , Fatores de RiscoRESUMO
Pregnancy represents a critical period in fetal development, such that the prenatal environment can, in part, establish a lifelong trajectory of health or disease for the offspring. Poor nutrition (macro- or micronutrient deficiencies) can adversely affect brain development and significantly increase offspring risk for metabolic and neurological disease development. The concentration of dietary methyl-donor nutrients is known to alter DNA methylation in the brain, and alterations in DNA methylation can have long-lasting effects on gene expression and neuronal function. The decreased availability of methyl-donor nutrients to the developing fetus in models of poor maternal nutrition is one mechanism hypothesized to link maternal malnutrition and disease risk in offspring. Animal studies indicate that supplementation of both maternal and postnatal (early- and later-life) diets with methyl-donor nutrients can attenuate disease risk in offspring; however, clinical research is more equivocal. The objective of this review is to summarize how specific methyl-donor nutrient deficiencies and excesses during pre- and postnatal life alter neurodevelopment and cognition. Emphasis is placed on reviewing the current literature, highlighting challenges within nutrient supplementation research, and considering potential strategies to ensure robust findings in future studies.
Assuntos
Cognição/fisiologia , Metilação de DNA/fisiologia , Suplementos Nutricionais , Fenômenos Fisiológicos da Nutrição Materna , Nutrientes/genética , Animais , Feminino , Desenvolvimento Fetal , Expressão Gênica , Humanos , Gravidez , Cuidado Pré-Natal/métodosRESUMO
One carbon metabolism is regulated by the availability of nutrients known as methyl donors, and disruption of this pathway can affect multiple physiological systems. DNA methylation, critical for the regulation of gene expression, is linked to one carbon metabolism, and can be altered by perinatal diet. In this study, dams (n = 12/group) were fed HF or standard control (SC) diet through pregnancy and lactation, and male and female offspring were then fed either SC or methyl donor-supplemented diet (MDS) between 3 and 6 weeks of age (n = 20-26/group). Concentration of one carbon intermediates and other related metabolites were assessed within brain tissue (prefrontal cortex, PFC) through the use of mass spectrometry at 6 weeks of age. In addition, the expression of target genes and enzymes that participate in DNA methylation or are relevant to one carbon metabolism were measured. We found that MDS increases the concentration of folate intermediates in the PFC, and that this increase is blunted in male offspring from dams fed a HF diet. In addition, perinatal HF diet increased the concentration of cysteine in the PFC of both male and female offspring, consistent with oxidative stress. Furthermore, both maternal HF diet and postnatal MDS altered global DNA methylation in the PFC in males but not females. Collectively, these data demonstrate sex differences in changes in one carbon metabolites in the prefrontal cortex in response to early life high fat diet and methyl donor supplementation. Read the Editorial Highlight for this article on page 358.
Assuntos
Encéfalo/metabolismo , Carbono/metabolismo , Suplementos Nutricionais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Metilação de DNA/fisiologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Expressão Gênica/fisiologia , Masculino , Camundongos , Gravidez , Caracteres SexuaisRESUMO
INTRODUCTION: Multiple Sclerosis (MS) is a chronic, inflammatory, neurodegenerative demyelinating disease of the central nervous system (CNS). Unfortunately, MS causes important disability in young adults and its prevalence is increasing. While the etiology of MS etiology is not completely understood, it seems to be a multifactorial entity that is influenced by both genetic and epigenetic modifications. Epigenetic mechanisms add or remove different chemical groups for the activation or inhibition of gene expression to block the production of proinflammatory proteins. It is truly important to identify the factors that can trigger epigenetic changes in MS to complement the therapeutic approach, prevent disability and improve patients quality of life. Here, we have conducted a review of external factors that influence in MS and their epigenetic mechanisms. For example, hypomethylation can promote changes in the myelin and subsequent autoimmune reactions. Therapeutic tools can be used, including the histone deacetylase inhibitor Trichostatin A, which ameliorates demyelinating diseases in rodents. However, drugs are not only the therapeutic option: recent studies have also evaluated the therapeutic potential of several bioactive dietary components in neurodegeneration and axonal dysfunction. Numerous food-derived molecules exert important metabolic actions. These molecules include plant polyphenols such as catechins and isoflavones, Ω-3 and Ω-6 polyunsaturated fatty acids, short-chain fatty acids, sulfur-containing compounds such as dally sulfide and other compounds. Antioxidant and anti-inflammatory components in the diet involve transcription factors as well. However, many external factors have shown to influence MS, although no specific epigenetic mechanisms are known. CONCLUSION: In this review, we gather both established and new evidences about the genetic, epigenetic and environmental factors influencing MS and the dietary components that could modulate MS relapse and progression.
Assuntos
Antioxidantes/administração & dosagem , Epigênese Genética/fisiologia , Esclerose Múltipla/dietoterapia , Esclerose Múltipla/metabolismo , Polifenóis/administração & dosagem , Animais , Antioxidantes/metabolismo , Metilação de DNA/fisiologia , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/administração & dosagem , Ácidos Graxos Ômega-6/metabolismo , Humanos , Esclerose Múltipla/genética , Polifenóis/metabolismoRESUMO
Muscle atrophy with aging is closely associated with chronic systemic inflammation and lifestyle-related diseases. Here, we assessed whether dried tofu intake during 5-month interval walking training (IWT) enhanced increases in thigh muscle mass and strength and ameliorated susceptibility to inflammation in older women. Subjects (n = 32, ~ 65 years) who performed IWT for > 6 months participated in this study. They were randomly divided into 2 groups: IWT + placebo intake (PLG, n = 16; 108 kcal, 0.2 g protein, 5.5 g fat, and 14.4 g carbohydrate) and IWT + dried tofu intake (DTG, n = 16; 111 kcal, 9.6 g protein, 6.0 g fat, and 4.6 g carbohydrate). They were instructed to repeat ≥ 5 sets of fast and slow walking for 3 min each at ≥ 70 and 40% peak aerobic capacity for walking, respectively, per day for ≥ 4 days/week. Immediately after daily exercise, subjects were instructed to consume the supplements assigned to each group. In the DTG, after IWT, the methylation increased at 4/6 sites in the promoter region of the NFKB2 gene in the whole blood (all, P < 0.04), with an 18% increase in the average methylation of the 6 sites (P = 0.035). On the other hand, in the PLG, the increase occurred at only 2/6 sites, with no significant increase in the average methylation of the 6 sites. No significant differences were observed in increases in thigh muscle strength or cross-sectional area between the groups (all, P > 0.2). Altogether, dried tofu supplementation during IWT likely enhanced the methylation of the NFKB2 gene more than IWT alone, without detectably enhanced increases in thigh muscle strength or cross-sectional area.